Should we control variability in how infants are treated for pain?
Myron Yaster MD, Rita Agarwal MD, Elliot J. Krane MD, and Lynne G. Maxwell MD
Many years ago, Dr. Peter Davis, Professor of Anesthesiology, Perioperative Medicine, and Pediatrics at UPMC Children's Hospital of Pittsburgh, gave a lecture at a SPA meeting on “managing variance” in anesthetic practice. He used the example of an airline flight from Pittsburgh to a city about a 1 hour flight away. He noted that no matter how delayed the takeoff, the plane always landed within a few minutes of its expected arrival time. How could this be? He explained that the airline had years of data on take-off and landing times, flight duration, the effects of weather etc. They assembled this data to produce travel schedules that accounted for all of these variables to reliably predict arrival times. How different it is in medicine. He urged the audience to gather data to manage variance in our daily practice.
In today’s PAAD, Keane et al.1 and Hadland snd Schiff2 in an invited commentary discuss the wide variability in opioid administration in sick newborn infants and urge their readers to develop and implement national protocols to reduce opioid administration variability. After reading the articles I could close my eyes and hear Peter’s voice in my head. Finally, for those of you who want to take a deeper dive into this subject, the authors have provided extensive bibliographies that can help guide you. Myron Yaster MD
Original article
Keane OA, Ourshalimian S, Lakshmanan A, Lee HC, Hintz SR, Nguyen N, Ing MC, Gong CL, Kaplan C, Kelley-Quon LI. Institutional and Regional Variation in Opioid Prescribing for Hospitalized Infants in the US. JAMA Netw Open. 2024 Mar 4;7(3):e240555. doi: 10.1001/jamanetworkopen.2024.0555. PMID: 38470421; PMCID: PMC10936113.
Editorial/Invited commentary
Hadland SE, Schiff DM. Opioids in Hospitalized Infants-Managing Pain and Sedation While Avoiding Overuse. JAMA Netw Open. 2024 Mar 4;7(3):e240523. doi: 10.1001/jamanetworkopen.2024.0523. PMID: 38470425.
“Pain management in hospitalized infants needs to balance 2 key considerations.3 First, infants with serious medical conditions often undergo painful interventions in the hospital (eg, surgical procedures, line placements, intubations, mechanical ventilation, ECMO, etc.), and clinicians must carefully manage infants’ pain and sedation to prevent distress and adverse long-term developmental consequences, including altered pain responses. Second, adequate pain control and sedation in infants who are critically ill often requires opioids, but high doses and durations of opioids in infants are associated with adverse health and neurocognitive outcomes. These 2 considerations are often in tension and likely contribute to differing clinical approaches across hospitals. Analysis of institutional variability in their use of opioids in infants is a critical first step in establishing clinical standards and supporting quality improvement.” This study by Keane and colleagues1 reports the findings of a large cohort study of medically complex infants aged younger than 1 year at 47 children’s hospitals across the US between 2016 and 2022 and highlights significant variation in opioid use among institutions.
Keane et al1 identified a sample of infants who were medically complex based on diagnoses of or procedures for congenital heart disease, necrotizing enterocolitis, extremely or very low birth weight, hypoxemic ischemic encephalopathy, extracorporeal membrane oxygenation, and other abdominal surgical procedures (infants with cancer and those exposed to opioids or other substances in utero were excluded). Keane et al1 found that more than 75% of these infants received opioids during their hospitalization, particularly fentanyl or morphine, with a median (IQR) of 5 (2-12) days of cumulative use. Clinical factors associated with more cumulative days of opioid use included mechanical ventilation, intensive care unit (ICU) or neonatal ICU stay, and medical complexity.”2
Where did the data come from? “A cohort of high-risk infants younger than 1 year at the time of admission from January 1, 2016, to December 31, 2022, was identified using the Pediatric Health Information Systems (PHIS) database.4 The PHIS database is maintained by the Children’s Hospital Association and includes clinical and resource utilization data for both inpatient and outpatient encounters for more than 47 children’s hospitals across the US. Hospitals registered in the PHIS database include freestanding children’s hospitals and large pediatric hospitals within an academic health system.”1
OK, what did they find? There was widespread variation in opioid prescribing by region and within individual institutions. Not surprisingly, patients with congenital heart disease, surgical necrotizing enterocolitis, on ECMO, extremely low birth weight as well as any patient requiring sedation for mechanical ventilation had the highest cumulative opioid days of therapy. The PHIS database did not provide information about cumulative opioid dosing. They also found that female sex, Asian race, and private insurance status are associated with fewer cumulative opioid days.
Aside from treating postoperative and procedural pain, many (most?) of the patients received opioids for sedation while they were being ventilated or on ECMO. Since my early days as pediatric anesthesiologist/intensivist I (MY) have often wondered why? And why do they require such staggeringly high doses? A common explanation is the development of tolerance. I (MY) don’t believe this and think the reason is much simpler. It’s the endotracheal tube and the inability to sleep while nursed in an ICU. Why do patients need to be awakened in the middle of the night for X-rays to be available on rounds in the morning? Why do patients, other than ECMO patients, need to be absolutely motionless? Would a simple tracheostomy prevent the need for so much sedation?
Opioid tolerance leads to an increase in dose requirement as much as 10x over the space of days while sedating newborns. The reason is that opioids are excellent analgesics but not good sedatives. The strong genetic basis for tolerance (see below) follows from evolutionary biology, in that pharmacololgic tolerance of physiological functions that are important for the survival of a species (e.g. alertness, breathing) develops rapidly, while tolerance of functions not essential for survival of a species (e.g. pooping) develops slowly, if ever at all. In a herd of gazelles grazing on plants that contain pharmacologically active alkaloids, it is more important to remain alert to the presence of predators than to stop to have a bowel movement while being chased by lions across a savannah. Thus in humans, opioid tolerance of constipation may never occur, while of sedation and respiratory depression it occurs relatively rapidly.5
Our friend and colleague Dr. Sapna Kudchadkar at Johns Hopkins has been working on this question for several years with promising non-pharmacologic intervention results and simply getting patients out of bed.6-8
Keane et al.1 suggest “Genetic variants in opioid receptors and stress response genes have been found to be associated with differences in infant pharmacologic treatment responses and length of hospitalization.3-5 Investigations into genetic predisposition to poor opioid response have been conducted in infants receiving mechanical ventilation. A study by Elens et al4 concluded that specific genetic alleles predispose premature infants to diminished opioid-induced pain relief. Further investigation of genetic factors that influence opioid response in high-risk infants could explain the variability in opioid prescribing attributed to unknown factors. In addition, genetic polymorphism can be responsible for a preponderance of the M3G metabolite (excitatory) vs M6G (analgesic, sedating) of morphine metabolism, causing irritabllity which may be misinterpreted as pain, especially in preterm infants early in life.
In addition, as pointed out in the accompanying editorial, the need for standardization of opioid administration parallels recent experience with attempts to standardize management of neonatal opioid withdrawal after in utero exposure. Care for a related condition, neonatal opioid withdrawal syndrome from in utero opioid exposure,9 has similarly shown substantial variability across institutions, with large differences nationwide in the percentage of infants receiving opioid agonist treatment and duration of treatment.10 This variability spurred national recommendations for hospitals to standardize their care, including enacting institutional policies, developing novel standardized clinical assessment tools, maximizing nonpharmacologic approaches and nonopioid medications, involving parents in care and comfort, and having clear clinical targets to guide the discontinuation of opioids, when used.2 Indeed, in the PHIS database examined by Keane et al, methadone may be used primarily to manage opioid withdrawal. The editorial also points out that such standardization would not only encompass recommendations for opioid administration under the umbrella of opioid stewardship, but would also require “harmonization in their use of assessment tools”2 including ancillary measures of reasons for infant distress other than pain. They conclude: “since under treated pain and excessive opioid use are both associated with adverse health and neurocognitive outcomes, striking a balance is critical."
As we’ve discussed in previous PAADs, a significant limitation of this database study, which the authors recognize, is “there is little context for the variation observed, and conjecture is required to deduce prescribing choices. Similarly, clinician variability and clinician-level characteristics and practices are not examined within this study and may have contributed to the observed institutional variation. The use of multimodal pain management strategies, including nonopioid pain medications, regional anesthetics, and nonpharmacologic interventions, was also not examined and may have influenced variation.”1
The authors conclude that “These findings highlight a need to develop standardized evidence-based protocols to manage procedural pain, prolonged intubation, and surgical recovery for high-risk infants. Clinical subgroups, including those with surgical NEC, ECMO, CHD, and ELBW and those undergoing abdominal surgery, have increased risk of prolonged opioid exposure and may benefit the most from standardization.”1 Finally, one of the assumptions of these papers is that prolonged and cumulative use of opioids will affect neurodevelopment. To be honest, we are not so sure. Almost all of the patients in this study were also treated with benzodiazepines and had other reasons to explain why they may be at risk for poor neurodevelopmental outcomes, such as hypoxia, hypotension, low cardiac output states, CHD, etc. Opioids remain a convenient target …they live in a “bad neighborhood”.
We’d like to remind all of you how terrible the treatment of childhood cancer would be today, if 40 years ago, pediatric oncologists across the country hadn’t joined together in a consortium to protocolize therapy, measure outcomes and manage variability. Of course, they had ample funding from governmental and pharmaceutical industry sources, something unlikely to be reproduced in this time for this reason. Nevertheless, isn’t it about time we did the same for pain and sedation management in our sickest newborn infants?
Send your thoughts and comments to Myron who will post in a Friday reader response.
References
1. Keane OA, Ourshalimian S, Lakshmanan A, et al. Institutional and Regional Variation in Opioid Prescribing for Hospitalized Infants in the US. JAMA network open 2024;7(3):e240555. (In eng). DOI: 10.1001/jamanetworkopen.2024.0555.
2. Hadland SE, Schiff DM. Opioids in Hospitalized Infants-Managing Pain and Sedation While Avoiding Overuse. JAMA network open 2024;7(3):e240523. (In eng). DOI: 10.1001/jamanetworkopen.2024.0523.
3. Balyan R, Zhang X, Chidambaran V, et al. OCT1 genetic variants are associated with postoperative morphine-related adverse effects in children. Pharmacogenomics 2017;18(7):621-629. (In eng). DOI: 10.2217/pgs-2017-0002.
4. Elens L, Norman E, Matic M, Rane A, Fellman V, van Schaik RH. Genetic Predisposition to Poor Opioid Response in Preterm Infants: Impact of KCNJ6 and COMT Polymorphisms on Pain Relief After Endotracheal Intubation. Therapeutic drug monitoring 2016;38(4):525-33. (In eng). DOI: 10.1097/ftd.0000000000000301.
5. Gaddis N, Mathur R, Marks J, et al. Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond. Sci Rep 2022;12(1):16873. (In eng). DOI: 10.1038/s41598-022-21003-y.
6. Patel RV, Redivo J, Nelliot A, et al. Early Mobilization in a PICU: A Qualitative Sustainability Analysis of PICU Up! Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2021;22(4):e233-e242. (In eng). DOI: 10.1097/pcc.0000000000002619.
7. Berger J, Zaidi M, Halferty I, Kudchadkar SR. Sleep in the Hospitalized Child: A Contemporary Review. Chest 2021;160(3):1064-1074. (In eng). DOI: 10.1016/j.chest.2021.04.024.
8. Kudchadkar SR, Aljohani O, Johns J, et al. Day-Night Activity in Hospitalized Children after Major Surgery: An Analysis of 2271 Hospital Days. The Journal of pediatrics 2019;209:190-197.e1. (In eng). DOI: 10.1016/j.jpeds.2019.01.054.
9. Patrick SW, Barfield WD, Poindexter BB; COMMITTEE ON FETUS AND NEWBORN, COMMITTEE ON SUBSTANCE USE AND PREVENTION. Neonatal Opioid Withdrawal Syndrome. Pediatrics. 2020 Nov;146(5):e2020029074. doi: 10.1542/peds.2020-029074. PMID: 33106341.
10. Young LW, Hu Z, Annett RD, Das A, Fuller JF, Higgins RD, Lester BM, Merhar SL, Simon AE, Ounpraseuth S, Smith PB, Crawford MM, Atz AM, Cottrell LE, Czynski AJ, Newman S, Paul DA, Sánchez PJ, Semmens EO, Smith MC, Turley CB, Whalen BL, Poindexter BB, Snowden JN, Devlin LA; EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT NEONATAL RESEARCH NETWORK AND THE NIH ENVIRONMENTAL INFLUENCES ON CHILD HEALTH OUTCOMES (ECHO) PROGRAM INSTITUTIONAL DEVELOPMENT AWARDS STATES PEDIATRIC CLINICAL TRIALS NETWORK. Site-Level Variation in the Characteristics and Care of Infants With Neonatal Opioid Withdrawal. Pediatrics. 2021 Jan;147(1):e2020008839. doi: 10.1542/peds.2020-008839. Epub 2020 Dec 21. PMID: 33386337; PMCID: PMC7780957.