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Caring for the Critically Ill Patient |

Epidemiology and Treatment of Painful Procedures in Neonates in Intensive Care Units FREE

Ricardo Carbajal, MD, PhD; André Rousset, MD; Claude Danan, MD; Sarah Coquery, MD; Paul Nolent, MD; Sarah Ducrocq, MD; Carole Saizou, MD; Alexandre Lapillonne, MD, PhD; Michèle Granier, MD; Philippe Durand, MD; Richard Lenclen, MD; Anne Coursol, MD; Philippe Hubert, MD, PhD; Laure de Saint Blanquat, MD; Pierre-Yves Boëlle, PhD; Daniel Annequin, MD; Patricia Cimerman, RN; K. J. S. Anand, MBBS, DPhil; Gérard Bréart, MD, PhD
[+] Author Affiliations

Author Affiliations: Centre National de Ressources de lutte contre la Douleur (Dr Carbajal and Ms Cimerman), Unité de réanimation néonatale et pédiatrique (Dr Nolent), and Unité fonctionnelle d'analgésie pédiatrique (Dr Annequin), Assistance Publique, Hôpitaux de Paris, Hôpital Armand Trousseau; Epidemiological Research Unit on Perinatal and Women's Health (Drs Carbajal and Bréart), INSERM UMR S149, Assistance Publique, Hôpitaux de Paris, Hôpital Tenon; Unité de réanimation néonatale, CHI André Grégoire, (Dr Rousset); Unité de réanimation néonatale, Centre hospitalier général intercommunal de Créteil (Dr Danan); Unité de réanimation néonatale, Assistance Publique, Hôpitaux de Paris, Hôpital Antoine Béclère (Dr Coquery); Unité de réanimation néonatale, Assistance Publique, Hôpitaux de Paris, Hôpital Cochin-Port Royal (Dr Ducrocq); Unité de réanimation néonatale et pédiatrique, Assistance Publique, Hôpitaux de Paris, Hôpital Robert Debré (Dr Saizou); Unité de réanimation néonatale et pédiatrique (Dr Lapillonne) and Unité de réanimation chirurgicale (Dr de Saint Blanquat) Assistance Publique, Hôpitaux de Paris, Hôpital Saint Vincent de Paul; Unité de réanimation néonatale, Hôpital Louise Michel (Dr Granier), Unité de réanimation néonatale et pédiatrique, Assistance Publique, Hôpitaux de Paris, Hôpital Bicêtre (Dr Durand); Unité de réanimation néonatale, CHI Poissy Saint Germain en Laye (Dr Lenclen); Unité de réanimation néonatale, Centre hospitalier René Dubos (Dr Coursol); Unité de réanimation néonatale et pédiatrique, Assistance Publique, Hôpitaux de Paris, Hôpital Necker-Enfants malades (Dr Hubert); Département de Santé Publique, Assistance Publique, Hôpitaux de Paris, Hôpital Saint Antoine, INSERM UMR S707, and UPMC, UMR S 707 (Dr Boëlle), Paris, France, and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock (Dr Anand).


JAMA. 2008;300(1):60-70. doi:10.1001/jama.300.1.60.
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Context Effective strategies to improve pain management in neonates require a clear understanding of the epidemiology and management of procedural pain.

Objective To report epidemiological data on neonatal pain collected from a geographically defined region, based on direct bedside observation of neonates.

Design, Setting, and Patients Between September 2005 and January 2006, data on all painful and stressful procedures and corresponding analgesic therapy from the first 14 days of admission were prospectively collected within a 6-week period from 430 neonates admitted to tertiary care centers in the Paris region of France (11.3 millions inhabitants) for the Epidemiology of Procedural Pain in Neonates (EPIPPAIN) study.

Main Outcome Measure Number of procedures considered painful or stressful by health personnel and corresponding analgesic therapy.

Results The mean (SD) gestational age and intensive care unit stay were 33.0 (4.6) weeks and 8.4 (4.6) calendar days, respectively. Neonates experienced 60 969 first-attempt procedures, with 42 413 (69.6%) painful and 18 556 (30.4%) stressful procedures; 11 546 supplemental attempts were performed during procedures including 10 366 (89.8%) for painful and 1180 (10.2%) for stressful procedures. Each neonate experienced a median of 115 (range, 4-613) procedures during the study period and 16 (range, 0-62) procedures per day of hospitalization. Of these, each neonate experienced a median of 75 (range, 3-364) painful procedures during the study period and 10 (range, 0-51) painful procedures per day of hospitalization. Of the 42 413 painful procedures, 2.1% were performed with pharmacological-only therapy; 18.2% with nonpharmacological-only interventions, 20.8% with pharmacological, nonpharmacological, or both types of therapy; and 79.2% without specific analgesia, and 34.2% were performed while the neonate was receiving concurrent analgesic or anesthetic infusions for other reasons. Prematurity, category of procedure, parental presence, surgery, daytime, and day of procedure after the first day of admission were associated with greater use of specific preprocedural analgesia, whereas mechanical ventilation, noninvasive ventilation and administration of nonspecific concurrent analgesia were associated with lower use of specific preprocedural analgesia.

Conclusion During neonatal intensive care in the Paris region, large numbers of painful and stressful procedures were performed, the majority of which were not accompanied by analgesia.

Figures in this Article

Repeated invasive procedures occur routinely in neonates who require intensive care, causing pain at a time when it is developmentally unexpected.1 Neonates are more sensitive to pain than older infants, children, and adults,2 and this hypersensitivity is exacerbated in preterm neonates.3 Multiple lines of evidence suggest that repeated and prolonged pain exposure alters their subsequent pain processing, long-term development, and behavior.4,5 It is essential, therefore, to prevent or treat pain in neonates. Numerous pharmacological and nonpharmacological treatments can alleviate procedural pain in neonates.6 As a consequence, national7 and international6 evidence-based guidelines have been issued for preventing or treating neonatal pain and its adverse consequences.

The burden of procedural pain in the neonatal intensive care unit (NICU) has been reported in previous single-center studies811 and a multicenter study.12 The latter study was based on chart review and was not directly observational. Effective strategies to improve pain management in neonates require a better understanding of the epidemiology and management of procedural pain. We report epidemiological data on neonatal pain collected from a geographically defined region (the Paris region of France, Île-de-France, which accounts for 20% of the country's population), which was based on the direct bedside observation of neonates.

Study Centers

The EPIPPAIN study (Epidemiology of Procedural Pain in Neonates) was designed as a prospective observational study to collect around-the-clock bedside data on all painful or stressful procedures performed in neonates admitted to the participating units. All 14 tertiary care centers, NICUs and pediatric intensive care units (PICUs) in the Paris Region (land area of 12 012 square kilometers and 11.3 million inhabitants) were invited to participate and 13 accepted the invitation. Eight centers were university-affiliated hospitals and 5 were community hospitals, including 8 NICUs and 5 PICUs. All NICUs transferred surgical patients to the participating PICUs.

Medical and nurse coordinators were designated in each participating unit; an interactive multimedia compact disc (CD) was distributed to train and ensure the participation of all health care providers. This CD included the study protocol, a PowerPoint presentation about the study, and video presentations showing how to complete the study forms. Local coordinators presented this CD in each unit and copies were available so that the personnel had the opportunity to view it before or during the study.

All the participating units had developed their pain management protocols locally; no instructions were given to modify the standard of care for procedural pain management in neonates. The study protocol was reviewed by the local committee for the protection of human subjects. Because this was an observational study with no changes in the standard of care, the human subjects committee established that further approvals or parental consent were not required according to French law. The computerized data collection was approved by the French Data Protection Authority (Commission Nationale de l’Informatique et des Libertés).

Official demographic data were obtained from the National Institute for Statistics and Economic Studies and data on hospitalization from the Technical Hospitalization Information Agency.

Study Infants

During the first 14 days of admission to the participating units, prospective data were collected on all neonatal procedures causing pain, stress, or discomfort with the corresponding analgesic therapy. A 6-week data collection period for each unit was considered sufficient to study the practices of all rotating personnel and to minimize temporal changes in clinical practices. Inclusion criterion was neonatal admission to the unit during the recruitment period, including preterm neonates younger than 45 postconceptional weeks and term neonates younger than 28 days. There were no exclusion criteria for these neonates.

Demographic data, type, and duration of respiratory support, sedative and analgesic drugs administered concomitantly or preprocedure, and conditions related to each procedure (type, hour of the day, operator, parental presence) were collected. We also recorded repeat procedure attempts for procedures requiring more than 1 attempt before successful completion. This knowledge may help clinicians in developing analgesic approaches for these procedures as well as strategies to minimize the pain and stress following an initial failed attempt. Specific preprocedural analgesia included nonpharmacological (eg, sweet solutions, sucking) or pharmacological treatments (eg, single- or multiple-drug doses).

Nursing and medical staff at the bedside recorded all procedures on a specific form in real time. Local study coordinators ensured that all procedures were recorded. A customized data collection form listed 24 common painful and stressful procedures and the participating staff could also list any other procedure that they considered painful or stressful. A policy statement of the American Academy of Pediatrics and Canadian Paediatric Society13 clearly distinguishes painful and stressful procedures.

In our study, a procedure is defined as a medical, nursing, surgical, diagnostic, or therapeutic activity performed in the unit. Continuous therapies were not counted as procedures (eg, ventilation). Because the current definition of pain as “an unpleasant sensory and emotional experience associated with actual or potential damage, or described in terms of such damage”14 does not apply to neonates,15 we chose a published empirical approach to define pain. This describes pain as an inherent quality of life that appears early in ontogeny to serve as a signaling system for tissue damage.15 Thus, a procedure was considered painful if it invaded the neonate's bodily integrity, causing skin injury or mucosal injury from the introduction or removal of foreign material into airway or digestive or urinary tract. Other procedures that were considered painful by clinicians at the bedside were also registered.

Stressful procedures were defined as those that mainly caused physical uneasiness or annoyance, or disturbed the existent equilibrium between the neonate and its environment.1,16 To establish the final classification of all recorded procedures, an experienced group of 15 NICU nurses and physicians estimated the presumed pain induced by procedures on a 0 to 100 scale at the end of data collection; all procedures with mean scores higher than 40/100 were considered painful.

If neonates were discharged from the units before 14 days, data collection was stopped on the day of discharge. A clinical research assistant visited each unit 2 to 3 times a week during the study period to assess recruitment of all patients by checking logbooks, to help with collection of demographic data, and to verify from the patients' charts that all procedures were documented on the study datasheets.

Data Analyses

Data were double entered into a relational database (created with EpiData Entry, version 3.0, Odense, Denmark) and analyzed with SPSS, version 14 for Windows, (SPSS Inc, Chicago, Illinois). Following descriptive and summary statistics, logistic regression analyses were used to explore the possible factors associated with the administration of analgesia. Two models were constructed to examine the relationships between the independent variables and 2 dependent variables (ie, use of specific preprocedural analgesia and the use of any analgesia during procedures). Variables correlated with the dependent variables (P ≤ .2) or deemed clinically important were included in these logistic models, with stepwise backward elimination of the nonsignificant covariates. Independent variables included center, sex, gestational age, type of respiratory support, parental presence, severity of illness (assessed using the Clinical Risk Index for Babies score), the neonate's surgical status, day of hospitalization (day 1 vs day 2 to 14), time (day or night) of procedure, and category of procedure (ie, needle stick for vascular access, needle stick without vascular access, tracheal intubation, chest tube insertion and minor surgical procedures, other minor procedures, and tube insertion in natural cavities). Continuous analgesia was also included as a factor in the model for specific analgesia prior to procedure.

The fit of the logistic model was assessed using the Hosmer-Lemeshow goodness-of-fit test and the global test. The −2 log likelihood-ratio statistic was used to test that all regression parameters are 0. The models were characterized by the area under the receiver operating characteristic curve, with 95% confidence intervals (CIs; 0.5, no predictive value; 1.0, perfect prediction). Results of regression analyses are presented as point estimate odds ratios (ORs) with 2-sided 95% CIs. The a priori level of statistical significance was P < .05.

Between September 2005 and January 2006, the 13 participating units enrolled 430 neonates in the study: 309 (71.9%) from NICUs and 121 (28.1%) from PICUs. Each unit enrolled 100% of eligible neonates during the study period. A total of 323 neonates (75.1%) were admitted in the units within the first 24 hours after birth. During the study period, 304 neonates were transferred to level 2 and level 1 units. The mean (SD) length of study participation was 8.4 (4.6) calendar days and the observation period represented 3598 patient-days. A total of 175 (40.7%) neonates received mechanical (tracheal) ventilation, 76 (17.7%) neonates received noninvasive ventilation (nasal positive pressure), 128 (29.7%) received both types of respiratory support, and 51 (11.9%) did not receive respiratory support during the study period. The overall rate of mechanical tracheal ventilation was 70.5%, but it varied from 46.2% to 92% across units. Continuous sedative or analgesic infusions were administered to 213 neonates; 211 of these received mechanical ventilation. Table 1 lists the demographic characteristics of the study population.

Table Graphic Jump LocationTable 1. Demographic Characteristics of 430 Neonates

In 2005, the Paris Region registered 11 399 319 inhabitants and 176 521 births per year. The corresponding figures for all France (metropolitan) were 60 825 000 inhabitants and 772 841 births per year. There were, respectively, 4530 and 16 296 neonatal admissions to intensive care units (tertiary care centers) in the Paris Region and all France during this year, which represented 2.6% and 2.1% of births, respectively.

Number and Type of Procedures

During the study period, neonates experienced 60 969 procedures on the first attempt and 11 546 procedures as supplemental attempts. The first attempt procedures included 60 different procedures, classified into 2 groups: 42 413 (69.6%) painful procedures and 18 556 (30.4%) stressful procedures. There were 44 different painful and 16 different stressful procedures; 33 of 44 painful procedures were classified by their invasive nature as defined above, these accounted for 35 376 (83.4%) of painful procedures. The remaining 11 painful procedures were classified as such by the group of nurses and physicians. All stressful procedures satisfied the definition given above. During the study period, the mean (SD) number of all procedures per neonate was 141 (107) and the mean (SD) number of procedures per day of hospitalization was 16 (9). The median number of all procedures was 115 (interquartile range [IQR], 48-216; range, 4-613) and 16 (IQR, 9-24; range, 0-62) per day of hospitalization.

Of these, each neonate experienced a mean (SD) of 98 (78) painful procedures during the study period, with 12 (8) painful procedures per day of hospitalization. The corresponding median number of painful procedures was 75 (IQR, 36-145; range, 3-364) during the study period and 10 (IQR, 5-17; range, 0-51) per day of hospitalization.

Analgesic Treatments

Table 2 and Table 3 list the most common painful and stressful procedures respectively, showing the use of analgesia for each of these procedures.

Table Graphic Jump LocationTable 2. Analgesic Treatment of the 20 Most Frequent Painful Procedures Performed in 430 Neonatesa
Table Graphic Jump LocationTable 3. Analgesic Treatment of the 10 Most Frequent Stressful (Causing Discomfort, Non-Painful) Procedures Performed in 430 Neonatesa

Specific Analgesia for Painful Procedures. Infants received specific analgesia for a median of 20% (IQR, 8%-36%) of the painful procedures performed during the study period. Of the 430 infants, 122 (28%) received specific analgesia for fewer than 10% of a median of 114 (IQR, 41-178) painfu procedures that they experienced during the study period. Of the 42 413 painful procedures, 907 (2.1%) were performed with pharmacological-only therapy, 7734 (18.2%) with nonpharmacological-only therapy, 164 (0.4%) with both, and 33 608 (79.2%) without specific preprocedural analgesia (Table 2). The nonpharmacological interventions included administering a sweet solution 1478 times (3.5%), allowing nonnutritive sucking 4405 times (10.4%), administering a sweet solution and allowing sucking 2011 times (4.7%), or allowing skin-to-skin maternal contact 4 times (<0.1%). Specific pharmacological treatments included intravenous opioids: 512 doses (1.2%) of morphine; 145 (0.3%) of fentanyl, or 165 (0.4%) of other opioids and included topical eutectic mixutre of lidocaine and prilocaine (EMLA) cream 123 times (0.3%) or other drugs 131 times (0.3%). Some procedures were performed with more than 1 pharmacological treatment.

Specific Analgesia for Stressful Procedures. Of the 18 556 procedures causing stress or discomfort, 136 (0.7%) were performed with pharmacological-only therapy, 1077 (5.8%) with nonpharmacological-only therapy, 6 (<0.1%) with both, and 17 337 (93.4%) without specific preprocedural analgesia. Specific nonpharmacological approaches included administering a sweet solution 109 times (0.6%), allowing nonnutritive sucking 863 times (4.7%), both 104 times (0.6%), and skin-to-skin maternal contact 7 times (<0.1%). Specific pharmacological treatments included administering opioid boluses 109 times (0.6%) and other drugs 33 times (0.2%).

Nonspecific Concurrent Analgesia. Of the 42 413 painful procedures, 14 495 (34.2%) were performed while the neonate was receiving analgesic or anesthetic infusions for other reasons, 14 245 (98.3%) of which were for mechanical ventilation. The medications administered in this context included 6546 doses (15.4%) of morphine, 3762 (8.9%) of fentanyl, 2831 (6.7%) of sufentanil, 1309 (3.1%) of nalbuphine, 133 (0.3%) of ketamine, and 47 (0.1%) of thiopental. Some patients received more than 1 medication during the procedure. Of the 18 556 stressful procedures, 3144 (16.9%) were performed while the neonate was receiving analgesic or anesthetic infusions, including 1549 doses (8.3%) of morphine, 796 (4.3%) of fentanyl, 626 (3.4%) of sufentanil, 161 (0.9) of nalbuphine, 19 (0.1%) of ketamine, or 12 (<0.1%) of thiopental; some patients received more than 1 medication during the procedure.

Specific and Nonspecific Analgesia. Infants received “some form of analgesia,” ie, nonspecific concurrent analgesia, specific preprocedural analgesia, or both for 21 568 painful procedures (50.9%) and for 4232 stressful procedures (22.8%). The corresponding figures for the most common procedures are shown in Table 2 and Table 3.

Factors Associated With Analgesia Use. The use of analgesia varied greatly among centers; ranging from 4.8% to 49.6% for specific preprocedural analgesia, and from 25.8% to 85.8% for “some form of analgesia” during painful procedures. Table 4 shows analgesia treatment for painful procedures by center and type of intensive care unit.

Table Graphic Jump LocationTable 4. Analgesia Treatment for Painful Procedures Performed in 430 Neonates, by Center and Type of Intensive Care Unit

The adjusted ORs with 95% CIs derived from logistic models for the use of analgesia during painful procedures are shown in Table 5. Multivariate logistic regression analysis showed that prematurity, parental presence during procedures, neonates undergoing surgery, daytime performance (7 AM to 6 PM), and day of hospitalization (2-14 days) were associated with greater use of specific preprocedural analgesia, whereas mechanical ventilation, noninvasive ventilation, the administration of nonspecific concurrent analgesia, and a higher Clinical Risk Index for Babies score were associated with less frequent use of specific preprocedural analgesia. The use of analgesia was also associated with the category of procedure. Compared with insertion of tubes in natural cavities, the ORs for the use of preprocedural analgesia were 43.22 (95% CI, 38.43-48.60; P < .001) for needle stick with vascular access; 10.52 (95% CI, 9.77-11.33; P < .001) for needle stick without vascular access; 12.57 (95% CI, 8.06-19.60; P < .001) for tracheal intubation; 52.55 (95% CI, 20.93-131.96; P < .001) for chest tube insertion, minor surgery; and 2.91 (95% CI, 2.68-3.15; P < .001) for other minor procedures.

Table Graphic Jump LocationTable 5. Logistic Regression Models of Factors Associated With the Use of Analgesia During 42413 Painful Procedures in Neonates, Adjusted for Centers
Conditions During Procedures

Figure 1 and Figure 2 show, respectively, the numbers of painful and stressful procedures performed during the whole study period according to gestational age at birth. Figure 3 shows the number of painful procedures performed during each day of hospitalization. Regarding respiratory support, 32 436 of 60 969 procedures (53.2%) were performed while neonates were receiving conventional mechanical ventilation; 1440 (2.4%), high-frequency ventilation; 14 624 (24%), noninvasive ventilation; 239 (0.4%), extracorporeal membrane oxygenation; and 12 230 (20.1%), no respiratory support. Of the 60 969 procedures, only 3574 (5.9%) were performed in the presence of parents. Anxiolytics or sedatives were used prior to procedures in 7 (<0.1%) of the 18 556 stressful procedures and as a continuous infusion in 1434 (7.7%) of stressful procedures. The maximum numbers of painful procedures were high; for instance, one 26-week-old infant had 95 heel sticks, one 32-week-old infant had 153 tracheal aspirations, and a 37-week-old infant underwent 132 nasal aspirations.

Place holder to copy figure label and caption
Figure 1. Number of Painful Procedures During the First 14 Days of Admission
Graphic Jump Location

Each circle represents a participating neonate; each blue bar the median value; error bars, values that are less than 1.5 box lengths from the edge of the box; data markers above the upper error bar, outliers; and the boxes, 25th and 75th percentiles.
aRepresents the number of neonates contibuting data at each gestational age.

Place holder to copy figure label and caption
Figure 2. Number of Stressful Procedures During the First 14 Days of Admission
Graphic Jump Location

Each circle represents a participating neonate; each blue bar the median value; error bars, values that are less than 1.5 box lengths from the edge of the box; data markers above the upper error bar, outliers; and the boxes, 25th and 75th percentiles.
aRepresents the number of neonates contibuting data at each gestational age.

Place holder to copy figure label and caption
Figure 3. Median Numbers, Interquartile Ranges, and Extreme Values of Painful Procedures Performed per Day of Neonatal ICU or Pediatric ICU hospitalization
Graphic Jump Location

Procedures were counted per calendar day and no correction was made for the actual stay length of the first or last day of study. Circles represent outliers (values that are more than 1.5 box lengths from the edge of the box), and error bars, values less than 1.5 interquartile range from the end of the box. Numbers were calculated only with neonates present at each day.
aThe number of neonates contributing data at each day of hospitalization.
bEight neonates were discharged during the 14th day of hospitalization, thus 126 were hospitalized for more than 14 days.

Number of Attempts

The 11 546 supplemental attempts performed during procedures included 10 366 for painful procedures and 1180 for stressful procedures. Table 6 presents the total (first and supplemental) number of attempts performed for the most common painful procedures. Some painful procedures needed as many as 10 to 15 attempts for completion.

Table Graphic Jump LocationTable 6. Number of Attempts to Terminate Some of the Most Common Painful Procedures Performed in 430 Neonatesa

To our knowledge, this is the first prospective multicenter study in a geographically defined population that documents the epidemiology of neonatal painful and stressful procedures from data obtained at the bedside in real time around-the-clock. Neonates in this study were admitted to tertiary care centers serving a population of 11.3 million people of the largest region of France. The participation of 13 of 14 centers in this region, the uniformity of data collection at all centers, and 100% patient inclusion during the study period ensure that the study cohort was representative of the neonatal population requiring intensive care in the Paris region. The study cohort may also closely represent the corresponding neonatal population of all France although the admission rate to intensive care units was slightly lower in the whole country (2.6% vs 2.1% of births, respectively).

This regional study shows that neonates undergo numerous procedures that have been associated with pain and stress during the first 14 days of intensive care, that the frequency of painful procedures does not markedly decrease during the ICU stay, that some common procedures require 4 or more attempts to be terminated in almost one-fifth of neonates, and that many of the documented painful procedures were not accompanied by analgesia. The 430 neonates requiring intensive care experienced procedures causing pain, stress, or discomfort very frequently, with 60 969 first-attempt procedures and 11 546 repeat-attempt procedures occurring in a mean duration of 8.4 days. Of note, 126 neonates were still hospitalized when data collection was stopped on the 14th day after admission and thus no further data on procedures performed on these neonates were collected after this day. The maximum number of procedures counted per neonate were high, 613 for all procedures and 364 for only painful procedures.

Three single-center studies8,10,11 have reported the total number of procedures performed during the entire NICU stay. From England, Barker and Rutter11 reported a mean of 60 procedures per patient performed in 54 neonates. From the United States, Porter and Anand10 documented 7672 procedures performed in 144 neonates, whereas Benis and Suresh8 reported a total of 5663 procedures performed in 15 preterm infants. Two other studies have reported the number of procedures performed during a defined period of NICU stay.9,12 Johnston et al12 studied 239 neonates from 14 NICUs in Canada during a 1-week period (129 neonates were already in the units at the beginning of the survey); 2134 procedures were performed during this period with an average of 2 procedures per neonate per day, with some infants having up to 8 procedures per day. Simons et al9 found that 151 neonates admitted to a Dutch NICU underwent 19 674 procedures during the first 14 days of admission. On average, each neonate experienced 14 procedures per day.9

In our study, the mean number of painful and painful plus stressful procedures per day were 12 and 16, respectively; some neonates experiencing as many as 62 procedures per day. The comparison of the types of painful procedures recorded in our study can be made with 39,11,12 of these 5 studies. Of the 20 most common painful procedures documented in our study (representing 42 090 of 42 413 (99.2%) of painful procedures, Table 2), 13 were also documented in the study by Simons et al,9 8 in the study by Barker and Rutter,11 and 6 in the study by Johnston et al.12 The 13 types of painful procedures of our study that were also documented in the study by Simon et al9 represented 40 369 of our 42 413 painful procedures. The procedures documented in the other 2 studies represented a lower number of painful procedures than what was documented in our study; this was mainly because those studies did not include all the procedures included in our data collection. In contrast to Simons et al,9 we found that the number of procedures did not markedly decrease during the NICU stay. As shown in Figure 3, the number of painful procedures per neonate does not markedly change between the eighth and 14th days of hospitalization; 25% of neonates still hospitalized on the 14th day of admission had 14 or more painful procedures performed on that day.

Advances in neonatal care in recent decades with increased survival of immature and sick neonates have led to an increased number of invasive procedures that may cause pain in these vulnerable neonates. The prevention of pain in critically ill neonates is not only an ethical obligation, but it also averts immediate and long-term adverse consequences.13 Painful stimulation elicits graded physiologic and behavioral responses in newborns to increasingly invasive procedures,17 activation of the somatosensory cortex,1820, and neuroendocrine stress responses.21 Repetitive pain leads to altered pain sensitivity22 with dampened behavioral responses to pain reflecting interrupted development2325 or heightened peripheral sensitivity.3,5,26 Altered excitability may cause innocuous tactile stimuli (eg, routine handling, diaper changes, bathing) to be perceived as noxious or painful.27,28 Grunau et al29 found greater reactivity of preterm infants to endotracheal suctioning following more pain exposures on the previous day. Thus, strategies to reduce the number of procedures in neonates are needed urgently. The American Academy of Pediatrics recently emphasized the need to incorporate a principle of minimizing the number of painful disruptions in neonatal care protocols.13 Such strategies would aim at bundling interventions, eliminating unnecessary laboratory or radiographic procedures, using transcutaneous measurements when possible, and minimizing the number of procedures performed after failed attempts.13

This last point is of particular importance and becomes a quality issue in the delivery of neonatal intensive care. The burden of procedural pain is greatly aggravated by multiple attempts in sick neonates. In our study, some common procedures (such as insertions of intravenous cannulas, central catheters, or peripheral arterial lines) required 4 or more attempts in more than 18% of neonates. Procedural techniques must be modified in order to prevent neonatal pain.30 Studies must be designed to determine to what extent common painful procedures are necessary and to what degree it is possible to avoid pain, stress, and discomfort while appropriately medically managing the neonates. There is a paucity of research in this area. For example, endotracheal suctioning could be performed on individual need rather than a routine scheduled basis. In one study, when suction frequency was changed from every 6 to 12 hours during the initial ventilation of preterm neonates with respiratory distress syndrome, there was no increase in secretions or occluded tubes.31

Overall, only 20.8% of painful procedures were carried out with specific analgesia before the procedure. This specific analgesia varied according to the type of procedures. It was used in less than 10% of procedures such as tracheal aspiration, chest physiotherapy, or bladder compression; but used in approximately 70% of procedures such as venipuncture, arterial puncture, intravenous cannula, or central-line insertion. Specific analgesia was essentially nonpharmacological. Specific analgesia use in our study occurred more frequently than in a previous Canadian study12 (0.8% of invasive procedures), either resulting from increased awareness of neonatal pain among heath care providers, infrequent documentation of nonpharmacological interventions previously, or because of different practices in different countries. In line with recent guidelines,13 intensive care units should implement effective pain-prevention programs, which include pharmacological and nonpharmacological therapies for preventing the pain induced by routine minor and major procedures.

Analgesic treatments should be tailored to the invasiveness or presumed pain intensity of the procedure. For minor procedures shown in Table 2, the combination of oral sucrose/glucose with other nonpharmacological pain-reduction methods (eg, nonnutrive sucking) should be sufficient. For major procedures, while general nonpharmacological measures still apply, systemic analgesia with a rapidly acting opiate such as fentanyl is usually necessary. Topical anesthetics can be used to reduce pain associated with needle punctures but are ineffective for heel-stick pain. We also found that 34.2% of painful procedures were carried out while neonates were receiving nonspecific concurrent analgesia (mostly opioids for mechanical ventilation). Opioids have been increasingly used for sedation and analgesia in preterm neonates breathing with the aid of mechanical ventilation.32 The analgesic effect of morphine on the acute pain caused by invasive procedures in preterm neonates remains controversial. Although initial studies showed promising results,33 recent studies have found nonsignificant analgesic efficacy.34,35 Thus, the administration of continuous morphine infusions to preterm neonates does not eliminate the need for other analgesic approaches (eg, sucrose) that are effective against acute pain.35 During the study period, 303 neonates received mechanical ventilation (175 exclusively and 128 either before or after noninvasive ventilation). Of these, 211 (69.3%) received continuous sedative or analgesic infusions. The observed proportion seems high given the conclusions of a recent systematic analysis of published clinical trials stating that more research in mechanically ventilated preterm and full-term neonates is needed before the routine management of analgesia and sedation can be placed on a scientific footing.32 At the time of our study, French guidelines for the use of continuous sedation and analgesia in neonates breathing with the aid of a ventilator or for reducing painful procedures were not available.

We found that 0.7% of stressful procedures were performed with specific pharmacological analgesia administered prior to procedure. The administration of analgesic drugs for stressful, nonpainful, procedures is not adequate. All analgesic agents have adverse effects that will certainly outweigh benefits in this context. When using opioids, for instance, clinicians should be aware of adverse effects such as respiratory depression, decreased gastrointestinal motility, hypotension, urinary retention, and muscle rigidity.6 Therapeutic but also toxic effects of analgesics and anesthetics in the immature brain36 must be considered. Long-term effects of analgesic or anesthetic drugs depend on whether they are given in the presence or absence of painful stimulation.36 Thus, the effects of surgery without anesthesia as well as the effects of anesthesia without surgery may be detrimental for the developing brain.36

The logistic regression analyses showed that many factors were associated with the use of analgesia. Mechanical ventilation, noninvasive ventilation and the administration of nonspecific concurrent analgesia were associated with less frequent use of specific preprocedural analgesia. Regarding concurrent analgesia, it is likely that when neonates are receiving continuous infusions of analgesics, clinicians are less prone to use preprocedural analgesia. However, this view has been challenged recently.34,35 The independent factor that showed the strongest association with the use of analgesia was the category of procedure, with greater analgesia being used for more invasive procedures.

Interpretation of these results should acknowledge several limitations. First, although no instructions were given to health personnel to modify their standard of care for procedural pain, we cannot exclude that the mere fact of gathering information could have altered practices. Data collection extending over a relatively long period of 6 weeks may have minimized this tendency. Second, procedure-specific analgesia was sometimes given for a bundled intervention including many procedures. In this situation, it was not possible to know if one particular procedure had elicited the specific analgesia. For this analysis, we considered that all procedures of such a bundled intervention were performed with specific analgesia. Both of these biases tend to enhance the significance of our findings. Third, although local study coordinators ensured that all procedures were recorded, and a visiting research assistant ascertained that the recordings were consistent with the patients' medical records, we cannot exclude the possibility that some details such as analgesia use or number of attempts recorded in real time were inaccurate. This potential limitation is minimal, however, because there was a 100% inclusion rate and no inaccuracy was found during cross-checking. Finally, we did not measure pain directly during each one of the recorded procedures. This would have allowed us to classify painful and stressful procedures in a more objective manner. We considered that assessing pain for all procedures in real time and around the clock would heavily increase the workload of health care providers with the risk of poor compliance.

The number of painful procedures is so high that the first step to improve procedural pain management must significantly reduce these numbers. The knowledge that some vulnerable neonates underwent 153 tracheal aspirations or 95 heel sticks in a two-week period should elicit a thoughtful and relevant analysis on the necessity and the risk-benefit ratio of our clinical practices.

Corresponding Author: Ricardo Carbajal, MD, PhD, Centre National de Ressources de lutte contre la Douleur, Hôpital d'enfants Armand Trousseau, 26, av du Dr Netter, 75012 Paris, France (ricardo.carbajal@trs.aphp.fr).

Author Contributions: Dr Carbajal had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Carbajal, Anand.

Acquisition of data: Carbajal, Rousset, Danan, Coquery, Nolent, Ducrocq, Saizou, Lapillonne, Granier, Durand, Lenclen, Coursol, Hubert, de Saint Blanquat, Cimerman.

Analysis and interpretation of data: Carbajal, Lapillonne, Hubert, Boëlle, Annequin, Anand, Breárt.

Drafting of the manuscript: Carbajal, Hubert, Annequin, Cimerman.

Critical revision of the manuscript for important intellectual content: Carbajal, Rousset, Danan, Coquery, Ducrocq, Saizou, Lapillonne, Granier, Durand, Lenclen, Coursol, Hubert, de Saint Blanquat, Boëlle, Annequin, Cimerman, Anand, Breárt.

Statistical analysis: Carbajal, Granier, Boëlle, Breárt.

Obtained funding: Carbajal, Annequin.

Administrative, technical, or material support: Carbajal, Rousset, Danan, Coquery, Nolent, Ducrocq, Lapillonne, Granier, Durand, Coursol, Hubert, de Saint Blanquat, Annequin, Cimerman.

Study supervision: Carbajal, Cimerman.

Financial Disclosures: None reported.

Funding/Support: This study was supported by grant funds from the Fondation CNP, and the Fondation de France, France.

Role of the Sponsor: These funding agencies did not participate in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Additional Contributions: We gratefully acknowledge the contributions of the physicians, nurses, and other health care providers at the participating institutions. We also thank Brigitte Fauroux, MD, PhD, Pediatric Pulmonary Department, Assistance Publique, Hôpitaux, Hôpital Armand Trousseau, Research Unit INSERM S719, Université Pierre et Marie Curie-Paris, for her critical review of a preliminary version of the manuscript. She did not receive any compensation. We thank Pierre Metral, MD, from the Technical Hospitalization Information Agency for providing data from the PMSI French Database. He did not receive any compensation.

Anand KJS, Aranda JV, Berde CB,  et al.  Summary proceedings from the neonatal pain-control group.  Pediatrics. 2006;117(3 pt 2):S9-S22
PubMed
Anand KJS. Clinical importance of pain and stress in preterm neonates.  Biol Neonate. 1998;73(1):1-9
PubMed   |  Link to Article
Fitzgerald M, Millard C, MacIntosh N. Hyperalgesia in premature infants.  Lancet. 1988;1(8580):292
PubMed   |  Link to Article
Grunau R. Early pain in preterm infants: a model of long-term effects.  Clin Perinatol. 2002;29(3):373-394, vii-viii.
PubMed   |  Link to Article
Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia.  Pain. 1989;39(1):31-36
PubMed   |  Link to Article
Anand KJS. Consensus statement for the prevention and management of pain in the newborn.  Arch Pediatr Adolesc Med. 2001;155(2):173-180
PubMed   |  Link to Article
American Academy of Pediatrics,.  Canadian Paediatric Society, Prevention and Management of Pain and stress in the neonate. American Academy of Pediatrics. Committee on Fetus and Newborn. Committee on Drugs. Section on Anesthesiology. Section on Surgery. Canadian Paediatric Society. Fetus and Newborn Committee.  Pediatrics. 2000;105(2):454-461
PubMed   |  Link to Article
Benis MM, Suresh GK. Frequency of invasive procedures in very low birth weight (VLBW) infants in the neonatal intensive care unit (NICU) [Abstract].  Pediatr Res. 2001;49(4):392A
Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies? a prospective study of procedural pain and analgesia in neonates.  Arch Pediatr Adolesc Med. 2003;157(11):1058-1064
PubMed   |  Link to Article
Porter FL, Anand KJS. Epidemiology of pain in neonates.  Res Clin Forums. 1998;20(4):9-18
Barker DP, Rutter N. Exposure to invasive procedures in neonatal intensive care unit admissions.  Arch Dis Child Fetal Neonatal Ed. 1995;72(1):F47-F48
PubMed   |  Link to Article
Johnston CC, Collinge JM, Henderson SJ, Anand KJ. A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive care units.  Clin J Pain. 1997;13(4):308-312
PubMed   |  Link to Article
Batton DG, Barrington KJ, Wallman C. Prevention and management of pain in the neonate: an update.  Pediatrics. 2006;118(5):2231-2241
PubMed   |  Link to Article
 Pain terms: a list with definitions and notes on usage: recommended by the IASP Subcommittee on Taxonomy.  Pain. 1979;6(3):249-252
PubMed
Anand KJ, Craig KD. New perspectives on the definition of pain.  Pain. 1996;67(1):3-6
PubMed   |  Link to Article
Chrousos GP, Gold PW. The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis.  JAMA. 1992;267(9):1244-1252
PubMed   |  Link to Article
Porter FL, Wolf CM, Miller JP. Procedural pain in newborn infants: the influence of intensity and development.  Pediatrics. 1999;104(1):e13
PubMed   |  Link to Article
Slater R, Cantarella A, Gallella S,  et al.  Cortical pain responses in human infants.  J Neurosci. 2006;26(14):3662-3666
PubMed   |  Link to Article
Slater R, Boyd S, Meek J, Fitzgerald M. Cortical pain responses in the infant brain [reply].  Pain. 2006;123(3):332
PubMed   |  Link to Article
Bartocci M, Bergqvist LL, Lagercrantz H, Anand KJ. Pain activates cortical areas in the preterm newborn brain.  Pain. 2006;122(1-2):109-117
PubMed   |  Link to Article
Grunau RE, Holsti L, Haley DW,  et al.  Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU.  Pain. 2005;113(3):293-300
PubMed   |  Link to Article
Ruda MA, Ling QD, Hohmann AG, Peng YB, Tachibana T. Altered nociceptive neuronal circuits after neonatal peripheral inflammation.  Science. 2000;289(5479):628-631
PubMed   |  Link to Article
Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response.  Pediatrics. 1996;98(5):925-930
PubMed
Whitfield MF, Grunau RE. Behavior, pain perception, and the extremely low-birth weight survivor.  Clin Perinatol. 2000;27(2):363-379
PubMed   |  Link to Article
Grunau RE, Oberlander TF, Whitfield MF, Fitzgerald C, Lee SK. Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 weeks' postconceptional age.  Pediatrics. 2001;107(1):105-112
PubMed   |  Link to Article
De Lima J, Alvares D, Hatch DJ, Fitzgerald M. Sensory hyperinnervation after neonatal skin wounding: effect of bupivacaine sciatic nerve block.  Br J Anaesth. 1999;83(4):662-664
PubMed   |  Link to Article
Grunau R, Tu MT. Long-term consequences of pain in human neonates. In: Anand KJ, Stevens B, McGrath P, eds. Pain in Neonates and Infants. 3rd ed. Philadelphia, PA: Elsevier Science BV; 2007:45-55
Holsti L, Grunau RE, Oberlander TF, Whitfield MF. Prior pain induces heightened motor responses during clustered care in preterm infants in the NICU.  Early Hum Dev. 2005;81(3):293-302
PubMed   |  Link to Article
Grunau RE, Holsti L, Whitfield MF, Ling E. Are twitches, startles, and body movements pain indicators in extremely low birth weight infants?  Clin J Pain. 2000;16(1):37-45
PubMed   |  Link to Article
Allegaert K, Tibboel D. Shouldn't we reconsider procedural techniques to prevent neonatal pain?  Eur J Pain. 2007;11(8):910-912
PubMed   |  Link to Article
Wilson G, Hughes G, Rennie J, Morley C. Evaluation of two endotracheal suction regimes in babies ventilated for respiratory distress syndrome.  Early Hum Dev. 1991;25(2):87-90
PubMed   |  Link to Article
Aranda JV, Carlo W, Hummel P, Thomas R, Lehr VT, Anand KJ. Analgesia and sedation during mechanical ventilation in neonates.  Clin Ther. 2005;27(6):877-899
PubMed   |  Link to Article
Moustogiannis AN, Raju TN, Roohey T, McCulloch KM. Intravenous morphine attenuates pain induced changes in skin blood flow in newborn infants.  Neurol Res. 1996;18(5):440-444
PubMed
Simons SH, van Dijk M, van Lingen RA,  et al.  Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial.  JAMA. 2003;290(18):2419-2427
PubMed   |  Link to Article
Carbajal R, Lenclen R, Jugie M, Paupe A, Barton BA, Anand KJ. Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates.  Pediatrics. 2005;115(6):1494-1500
PubMed   |  Link to Article
Anand KJ, Soriano SG. Anesthetic agents and the immature brain: are these toxic or therapeutic?  Anesthesiology. 2004;101(2):527-530
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Number of Painful Procedures During the First 14 Days of Admission
Graphic Jump Location

Each circle represents a participating neonate; each blue bar the median value; error bars, values that are less than 1.5 box lengths from the edge of the box; data markers above the upper error bar, outliers; and the boxes, 25th and 75th percentiles.
aRepresents the number of neonates contibuting data at each gestational age.

Place holder to copy figure label and caption
Figure 2. Number of Stressful Procedures During the First 14 Days of Admission
Graphic Jump Location

Each circle represents a participating neonate; each blue bar the median value; error bars, values that are less than 1.5 box lengths from the edge of the box; data markers above the upper error bar, outliers; and the boxes, 25th and 75th percentiles.
aRepresents the number of neonates contibuting data at each gestational age.

Place holder to copy figure label and caption
Figure 3. Median Numbers, Interquartile Ranges, and Extreme Values of Painful Procedures Performed per Day of Neonatal ICU or Pediatric ICU hospitalization
Graphic Jump Location

Procedures were counted per calendar day and no correction was made for the actual stay length of the first or last day of study. Circles represent outliers (values that are more than 1.5 box lengths from the edge of the box), and error bars, values less than 1.5 interquartile range from the end of the box. Numbers were calculated only with neonates present at each day.
aThe number of neonates contributing data at each day of hospitalization.
bEight neonates were discharged during the 14th day of hospitalization, thus 126 were hospitalized for more than 14 days.

Tables

Table Graphic Jump LocationTable 1. Demographic Characteristics of 430 Neonates
Table Graphic Jump LocationTable 2. Analgesic Treatment of the 20 Most Frequent Painful Procedures Performed in 430 Neonatesa
Table Graphic Jump LocationTable 3. Analgesic Treatment of the 10 Most Frequent Stressful (Causing Discomfort, Non-Painful) Procedures Performed in 430 Neonatesa
Table Graphic Jump LocationTable 4. Analgesia Treatment for Painful Procedures Performed in 430 Neonates, by Center and Type of Intensive Care Unit
Table Graphic Jump LocationTable 5. Logistic Regression Models of Factors Associated With the Use of Analgesia During 42413 Painful Procedures in Neonates, Adjusted for Centers
Table Graphic Jump LocationTable 6. Number of Attempts to Terminate Some of the Most Common Painful Procedures Performed in 430 Neonatesa

References

Anand KJS, Aranda JV, Berde CB,  et al.  Summary proceedings from the neonatal pain-control group.  Pediatrics. 2006;117(3 pt 2):S9-S22
PubMed
Anand KJS. Clinical importance of pain and stress in preterm neonates.  Biol Neonate. 1998;73(1):1-9
PubMed   |  Link to Article
Fitzgerald M, Millard C, MacIntosh N. Hyperalgesia in premature infants.  Lancet. 1988;1(8580):292
PubMed   |  Link to Article
Grunau R. Early pain in preterm infants: a model of long-term effects.  Clin Perinatol. 2002;29(3):373-394, vii-viii.
PubMed   |  Link to Article
Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia.  Pain. 1989;39(1):31-36
PubMed   |  Link to Article
Anand KJS. Consensus statement for the prevention and management of pain in the newborn.  Arch Pediatr Adolesc Med. 2001;155(2):173-180
PubMed   |  Link to Article
American Academy of Pediatrics,.  Canadian Paediatric Society, Prevention and Management of Pain and stress in the neonate. American Academy of Pediatrics. Committee on Fetus and Newborn. Committee on Drugs. Section on Anesthesiology. Section on Surgery. Canadian Paediatric Society. Fetus and Newborn Committee.  Pediatrics. 2000;105(2):454-461
PubMed   |  Link to Article
Benis MM, Suresh GK. Frequency of invasive procedures in very low birth weight (VLBW) infants in the neonatal intensive care unit (NICU) [Abstract].  Pediatr Res. 2001;49(4):392A
Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies? a prospective study of procedural pain and analgesia in neonates.  Arch Pediatr Adolesc Med. 2003;157(11):1058-1064
PubMed   |  Link to Article
Porter FL, Anand KJS. Epidemiology of pain in neonates.  Res Clin Forums. 1998;20(4):9-18
Barker DP, Rutter N. Exposure to invasive procedures in neonatal intensive care unit admissions.  Arch Dis Child Fetal Neonatal Ed. 1995;72(1):F47-F48
PubMed   |  Link to Article
Johnston CC, Collinge JM, Henderson SJ, Anand KJ. A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive care units.  Clin J Pain. 1997;13(4):308-312
PubMed   |  Link to Article
Batton DG, Barrington KJ, Wallman C. Prevention and management of pain in the neonate: an update.  Pediatrics. 2006;118(5):2231-2241
PubMed   |  Link to Article
 Pain terms: a list with definitions and notes on usage: recommended by the IASP Subcommittee on Taxonomy.  Pain. 1979;6(3):249-252
PubMed
Anand KJ, Craig KD. New perspectives on the definition of pain.  Pain. 1996;67(1):3-6
PubMed   |  Link to Article
Chrousos GP, Gold PW. The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis.  JAMA. 1992;267(9):1244-1252
PubMed   |  Link to Article
Porter FL, Wolf CM, Miller JP. Procedural pain in newborn infants: the influence of intensity and development.  Pediatrics. 1999;104(1):e13
PubMed   |  Link to Article
Slater R, Cantarella A, Gallella S,  et al.  Cortical pain responses in human infants.  J Neurosci. 2006;26(14):3662-3666
PubMed   |  Link to Article
Slater R, Boyd S, Meek J, Fitzgerald M. Cortical pain responses in the infant brain [reply].  Pain. 2006;123(3):332
PubMed   |  Link to Article
Bartocci M, Bergqvist LL, Lagercrantz H, Anand KJ. Pain activates cortical areas in the preterm newborn brain.  Pain. 2006;122(1-2):109-117
PubMed   |  Link to Article
Grunau RE, Holsti L, Haley DW,  et al.  Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU.  Pain. 2005;113(3):293-300
PubMed   |  Link to Article
Ruda MA, Ling QD, Hohmann AG, Peng YB, Tachibana T. Altered nociceptive neuronal circuits after neonatal peripheral inflammation.  Science. 2000;289(5479):628-631
PubMed   |  Link to Article
Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response.  Pediatrics. 1996;98(5):925-930
PubMed
Whitfield MF, Grunau RE. Behavior, pain perception, and the extremely low-birth weight survivor.  Clin Perinatol. 2000;27(2):363-379
PubMed   |  Link to Article
Grunau RE, Oberlander TF, Whitfield MF, Fitzgerald C, Lee SK. Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 weeks' postconceptional age.  Pediatrics. 2001;107(1):105-112
PubMed   |  Link to Article
De Lima J, Alvares D, Hatch DJ, Fitzgerald M. Sensory hyperinnervation after neonatal skin wounding: effect of bupivacaine sciatic nerve block.  Br J Anaesth. 1999;83(4):662-664
PubMed   |  Link to Article
Grunau R, Tu MT. Long-term consequences of pain in human neonates. In: Anand KJ, Stevens B, McGrath P, eds. Pain in Neonates and Infants. 3rd ed. Philadelphia, PA: Elsevier Science BV; 2007:45-55
Holsti L, Grunau RE, Oberlander TF, Whitfield MF. Prior pain induces heightened motor responses during clustered care in preterm infants in the NICU.  Early Hum Dev. 2005;81(3):293-302
PubMed   |  Link to Article
Grunau RE, Holsti L, Whitfield MF, Ling E. Are twitches, startles, and body movements pain indicators in extremely low birth weight infants?  Clin J Pain. 2000;16(1):37-45
PubMed   |  Link to Article
Allegaert K, Tibboel D. Shouldn't we reconsider procedural techniques to prevent neonatal pain?  Eur J Pain. 2007;11(8):910-912
PubMed   |  Link to Article
Wilson G, Hughes G, Rennie J, Morley C. Evaluation of two endotracheal suction regimes in babies ventilated for respiratory distress syndrome.  Early Hum Dev. 1991;25(2):87-90
PubMed   |  Link to Article
Aranda JV, Carlo W, Hummel P, Thomas R, Lehr VT, Anand KJ. Analgesia and sedation during mechanical ventilation in neonates.  Clin Ther. 2005;27(6):877-899
PubMed   |  Link to Article
Moustogiannis AN, Raju TN, Roohey T, McCulloch KM. Intravenous morphine attenuates pain induced changes in skin blood flow in newborn infants.  Neurol Res. 1996;18(5):440-444
PubMed
Simons SH, van Dijk M, van Lingen RA,  et al.  Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial.  JAMA. 2003;290(18):2419-2427
PubMed   |  Link to Article
Carbajal R, Lenclen R, Jugie M, Paupe A, Barton BA, Anand KJ. Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates.  Pediatrics. 2005;115(6):1494-1500
PubMed   |  Link to Article
Anand KJ, Soriano SG. Anesthetic agents and the immature brain: are these toxic or therapeutic?  Anesthesiology. 2004;101(2):527-530
PubMed   |  Link to Article
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