OBJECTIVES

The primary objective was to evaluate hospital variation in intravenous (IV) acetaminophen use across pediatric patient populations. The secondary objective was to identify populations with high use of IV acetaminophen and wide variation in practice to identify priority areas for cost reduction and practice standardization.

METHODS

We performed a retrospective study of children ≤18 years old hospitalized in 2019 in 48 US pediatric hospitals in the Pediatric Health Information System. Primary measures included IV acetaminophen use (percentage of encounters) and total days of therapy (DOT). A multivariable analysis identified clinical and demographic factors associated with IV acetaminophen use. High-priority groups for practice standardization were the All Patient Refined Diagnosis Related Groups in the top quartile of DOT, with wide variation of use across hospitals (interquartile range >50%).

RESULTS

Among 866 346 encounters, 14.4% received 1 dose of IV acetaminophen with 287 935 DOT, costing $29.8 million. In multivariable analysis age, payer, surgical procedure, ICU admission, total parenteral nutrition, and case mix index remained significantly associated with IV acetaminophen use. After multivariable adjustment, variation in hospital use ranged from <0.1% to 31% of all encounters. Twenty diagnosis groups accounted for 47% of total DOT (135 910 days) and 48% of cost ($14.2 million). Appendectomy, tonsil and adenoidectomy, and craniotomy were identified as top candidates for standardization efforts.

CONCLUSIONS

We observed large variation in IV acetaminophen use across pediatric hospitals and within diagnosis groups. These diagnoses represent candidates for practice standardization.

Intravenous (IV) acetaminophen was approved by the US Food and Drug Administration in 2010 for the management of mild to moderate pain, severe pain in conjunction with opioids, and reduction of fever.1  The targeted marketing strategy for Cadence Pharmaceuticals was focused on significant pain relief, a presumed reduction in opioid consumption, improved patient satisfaction, and established safety profile.2  The IV formulation was launched at a considerably higher price point compared with the oral and rectal formulations in the context of a national focus on opioid-sparing analgesia because of the mounting opioid epidemic.36  Rapid formulary adoption and broad physician use expanded the use of the IV formulation across adult and pediatric hospitals to >2000 hospitals within the first 21 months.2  Furthermore, among adult patients, IV acetaminophen was estimated to increase from 0% in 2011 to 23% for patients with coronary artery bypass graft surgeries and 32% of patients with colectomies in 2013.6 

Within the pediatric population, the efficacy and clinical benefits of IV acetaminophen are not well established. Researchers in multiple single-center studies have demonstrated marginal clinical benefit when compared with placebo across pediatric indications.711  Despite the lack of evidence, use of pediatric IV acetaminophen has risen substantially, with researchers in 1 study indicating the total cost of acetaminophen treatment among hospitalized children had increased more than sixfold by 2017.12 

Patterns of IV acetaminophen use across pediatric conditions remain poorly defined. Our primary objective was to describe hospital-level variation in IV acetaminophen use among hospitalized pediatric patients. Our secondary objective was to identify pediatric patient populations with high use of IV acetaminophen and wide variation in practice patterns to identify priorities for cost reduction and practice standardization.

The Pediatric Health Information System (PHIS) database contains administrative and billing data from 49 tertiary, free standing, primarily academic (95%), pediatric hospitals affiliated with the Children’s Hospital Association (CHA) (Lenexa, KS). The median size of the pediatric hospital is 350 staffed beds with an average daily census of 230 patients. Encounter-level data include patient demographic characteristics; International Classification of Diseases, 10th Revision, Clinical Modification diagnostic and procedural codes; and date-stamped billing data for a wide range of clinical services including diagnostic tests and pharmaceuticals. Patients are assigned a unique identifier to permit tracking of multiple admissions to the same hospital. The quality of the data are managed with pre- and postsubmission audits that continue as a joint collaborative effort between CHA and the affiliated hospitals.13  We queried PHIS for inpatient and observation encounters for patients age 18 years or younger who were discharged between January 1, 2019, and December 31, 2019. Patients are assigned a unique identifier to permit tracking of multiple admissions to the same hospital.

Encounters from hospitals that did not submit complete data to PHIS were excluded. Encounters were categorized into clinically relevant groups by using All Patient Refined Diagnosis Related Groups (APR DRGs) v32.14 

We used PHIS pharmacy billing data to identify calendar days on which patients were billed for IV acetaminophen. We defined IV acetaminophen use as the percentage of encounters associated with administration of at least 1 dose of IV acetaminophen. We defined days of therapy (DOT) as the number of calendar days for which an encounter was billed for IV acetaminophen. The 20 APR DRGs with the highest total DOT across all hospitals were designated “high-use APR DRGs.” We calculated the IV acetaminophen costs by multiplying billed charges for IV acetaminophen by the respective hospital’s pharmacy-specific ratio of costs to charges, as reported on their hospital cost report submitted annually to the Centers for Medicare and Medicaid Services.15 

To adjust for differences in patient characteristics when comparing IV acetaminophen use across hospitals, we examined patient demographic and clinical variables that were potentially associated with higher use. These variables included age at admission (categorized into <1, 1–4, 5–12, 13–18 years), race and ethnicity (white, Black, Hispanic, other, and unknown), and primary insurance type (private versus public). International Classification of Diseases, 10th Revision, Clinical Modification diagnostic and procedural codes were used to identify patients with a complex chronic condition16 . The proprietary PHIS case mix index (CMI) served as another marker of disease severity.17  The CMI is an APR DRG–based resource intensity weight derived by CHA by using the HCUP (Healthcare Cost and Utilization Project) KID (Kid’s Inpatient Database) Database, a nationally representative sample of pediatric inpatient admissions.18  For a given APR DRG and severity of illness combination, the CMI is the ratio of the mean cost of hospitalization for that APR DRG severity of illness combination relative to the mean cost across all admissions to tertiary, pediatric hospitals across the United States. A CMI >1 indicates that the cost of that hospitalization is expected to be higher than average, and, conversely, a CMI <1 indicates an expected cost lower than average. We categorized patients in this study into deciles of CMI. Additional risk factors based on billed data included surgical procedure defined by the presence of an operating room charge, ICU admission, extracorporeal membrane oxygenation (ECMO), total parenteral nutrition (TPN), and mechanical ventilation.

We used logistic regression to estimate the univariate and multivariable associations between patient demographic and clinical characteristics and IV acetaminophen use. Generalized estimating equations were used to control for clustering within hospitals. The multivariable model was used to calculate rates of hospital-level IV acetaminophen use adjusted for variation in patient characteristics. We describe the hospital-level variation in IV acetaminophen use within each of the 20 high-use APR DRGs with medians and interquartile ranges (IQRs), defined as the difference between the 75th and 25th percentiles of hospital IV acetaminophen use. Within each APR DRG, hospitals with fewer than 20 encounters were excluded to ensure adequate volume of encounters. We defined high-priority APR DRGs for practice standardization as those with the high contributions to IV acetaminophen use (ie, top quartile in DOT across APR DRGs) accompanied by wide variation in IV acetaminophen use (ie, IQR across hospitals >50%). Statistical significance was achieved with a 2-sided P value <.05. Analyses were performed by using SAS System for Windows v9.4 (SAS Institute, Inc, Cary, NC).

In 2019, there were 879 869 inpatient and observation encounters from 49 hospitals in the PHIS database. A total of 13 523 encounters from 1 hospital that did not submit a complete year of data were excluded. The study cohort included 866 346 encounters for 677 497 unique patients (mean: 1.3 encounters per patient) from 48 hospitals with a total of 4 554 000 hospital days. The median number of encounters per hospital was 15 591 (range: 6500–40 428). Of those encounters, 125 456 (14.4%) received at least 1 dose of IV acetaminophen during the hospitalization, corresponding to a total of 287 935 DOT (6.3% of total hospital days) and a cost of $29.8 million.

In univariate analyses, patient characteristics associated with higher rates of IV acetaminophen use included older age (5–12 and 13–18 years versus <1 year: 18% vs 9%, P < .0001), non-Black race or ethnicity (white and Hispanic versus Black: 15% and 16% vs. 10%, P = .004), private versus public insurance (16% vs 13%, P = .01), complex chronic condition versus no complex chronic condition (21% vs 11%, P < .0001), surgical procedure during admission versus no surgical procedure (46% vs 5%, P < .0001), ICU admission versus no ICU admission (26% vs 12%, P < .0001), ECMO versus no ECMO (57% vs 14%, P < .0001), TPN versus no TPN (37% vs 13%, P < .0001), mechanical ventilation versus no mechanical ventilation (34% vs 13%, <.0001), and higher CMI (P = .0001) (Table 1). Age, payer, surgical procedure, ICU admission, TPN, and CMI remained significantly associated with IV acetaminophen use in the multivariable model.

TABLE 1

Association Between Patient Demographic and Clinical Characteristics and IV Acetaminophen Use

Total CasesEncounters Receiving IV Acetaminophen (%)Unadjusted Odds Ratio (95% CI)Unadjusted PAdjusted Odds Ratio (95% CI)Adjusted P
Age       
 <1 253 033 22 660 (9) <.0001 <.0001 
 1–4 208 177 29 277 (14) 1.7 (1.4–2)  2.1 (1.8–2.3)  
 5–12 222 293 40 365 (18) 2.3 (1.9–2.7)  2.2 (2–2.5)  
 13–18 182 843 33 154 (18) 2.3 (1.9–2.7)  2.3 (2–2.6)  
Race and ethnicity       
 White 401 432 60 305 (15) .004 .13 
 Black 164 274 16 568 (10) 0.6 (0.5–0.8)  0.8 (0.6–1)  
 Hispanic 174 712 27 579 (16) 1.1 (0.8–1.4)  1.2 (0.9–1.7)  
 Other 94 008 15 271 (16) 1.1 (0.9–1.4)  1.3 (1–1.7)  
 Unknown 31 920 5733 (18) 1.2 (0.7–2.2)  1.7 (1–2.7)  
Payer       
 Private 377 637 60 821 (16) .001 .03 
 Public 488 709 64 635 (13) 0.8 (0.7–0.9)  0.9 (0.7–1)  
Complex chronic condition       
 No 535 485 57 220 (11) <.0001 .07 
 Yes 330 861 68 236 (21) 2.2 (1.9–2.5) <.0001 0.9 (0.8–1)  
Surgical procedure       
 No 661 033 31 395 (5) <.0001 <.0001 
 Yes 205 313 94 061 (46) 17 (12.1–23.7) <.0001 10 (6.8–14.6)  
ICU       
 No 704 585 83 007 (12) <.0001 <.0001 
 Yes 161 761 42 449 (26) 2.7 (2.2–3.2) <.0001 1.9 (1.6–2.3)  
ECMO       
 No 864 472 124 385 (14) <.0001 .19 
 Yes 1874 1071 (57) 7.9 (5.1–12.5)  0.7 (0.4–1.2)  
TPN       
 No 825 292 110 366 (13) <.0001 <.0001 
 Yes 41 054 15 090 (37) 3.8 (3.2–4.5)  1.7 (1.5–1.9)  
Mechanical ventilation       
 No 803 684 104 240 (13) <.0001 .67 
 Yes 62 662 21 216 (34) 3.4 (2.9–4.1)  1 (0.9–1.2)  
CMI decile       
 ≤0.48 89 686 827 (1) .0001 .003 
 0.49–0.60 92 185 1756 (2) 2.1 (1.5–2.9)  1.4 (1.1–1.8)  
 0.61–0.71 80 767 3717 (5) 5.2 (3.9–6.9)  2.4 (1.9–3)  
 0.72–0.83 88 254 7860 (9) 10.5 (7.1–15.5)  3.9 (2.7–5.5)  
 0.84–1.08 84 179 6974 (8) 9.7 (7–13.4)  3.4 (2.5–4.5)  
 1.09–1.33 87 395 12 416 (14) 17.8 (12.7–24.9)  5.1 (3.7–7.1)  
 1.34–1.65 84 277 7768 (9) 10.9 (7.9–15)  3.8 (2.9–5.1)  
 1.66–2.43 87 778 25 127 (29) 43.1 (30.1–61.8)  7.2 (4.7–11)  
 2.44–4.86 85 495 21 858 (26) 36.9 (25.8–52.8)  8.1 (5.5–11.9)  
 ≥4.87 86 330 37 153 (43) 81.2 (55.6–118.4)  11.4 (7.1–18.4)  
Total CasesEncounters Receiving IV Acetaminophen (%)Unadjusted Odds Ratio (95% CI)Unadjusted PAdjusted Odds Ratio (95% CI)Adjusted P
Age       
 <1 253 033 22 660 (9) <.0001 <.0001 
 1–4 208 177 29 277 (14) 1.7 (1.4–2)  2.1 (1.8–2.3)  
 5–12 222 293 40 365 (18) 2.3 (1.9–2.7)  2.2 (2–2.5)  
 13–18 182 843 33 154 (18) 2.3 (1.9–2.7)  2.3 (2–2.6)  
Race and ethnicity       
 White 401 432 60 305 (15) .004 .13 
 Black 164 274 16 568 (10) 0.6 (0.5–0.8)  0.8 (0.6–1)  
 Hispanic 174 712 27 579 (16) 1.1 (0.8–1.4)  1.2 (0.9–1.7)  
 Other 94 008 15 271 (16) 1.1 (0.9–1.4)  1.3 (1–1.7)  
 Unknown 31 920 5733 (18) 1.2 (0.7–2.2)  1.7 (1–2.7)  
Payer       
 Private 377 637 60 821 (16) .001 .03 
 Public 488 709 64 635 (13) 0.8 (0.7–0.9)  0.9 (0.7–1)  
Complex chronic condition       
 No 535 485 57 220 (11) <.0001 .07 
 Yes 330 861 68 236 (21) 2.2 (1.9–2.5) <.0001 0.9 (0.8–1)  
Surgical procedure       
 No 661 033 31 395 (5) <.0001 <.0001 
 Yes 205 313 94 061 (46) 17 (12.1–23.7) <.0001 10 (6.8–14.6)  
ICU       
 No 704 585 83 007 (12) <.0001 <.0001 
 Yes 161 761 42 449 (26) 2.7 (2.2–3.2) <.0001 1.9 (1.6–2.3)  
ECMO       
 No 864 472 124 385 (14) <.0001 .19 
 Yes 1874 1071 (57) 7.9 (5.1–12.5)  0.7 (0.4–1.2)  
TPN       
 No 825 292 110 366 (13) <.0001 <.0001 
 Yes 41 054 15 090 (37) 3.8 (3.2–4.5)  1.7 (1.5–1.9)  
Mechanical ventilation       
 No 803 684 104 240 (13) <.0001 .67 
 Yes 62 662 21 216 (34) 3.4 (2.9–4.1)  1 (0.9–1.2)  
CMI decile       
 ≤0.48 89 686 827 (1) .0001 .003 
 0.49–0.60 92 185 1756 (2) 2.1 (1.5–2.9)  1.4 (1.1–1.8)  
 0.61–0.71 80 767 3717 (5) 5.2 (3.9–6.9)  2.4 (1.9–3)  
 0.72–0.83 88 254 7860 (9) 10.5 (7.1–15.5)  3.9 (2.7–5.5)  
 0.84–1.08 84 179 6974 (8) 9.7 (7–13.4)  3.4 (2.5–4.5)  
 1.09–1.33 87 395 12 416 (14) 17.8 (12.7–24.9)  5.1 (3.7–7.1)  
 1.34–1.65 84 277 7768 (9) 10.9 (7.9–15)  3.8 (2.9–5.1)  
 1.66–2.43 87 778 25 127 (29) 43.1 (30.1–61.8)  7.2 (4.7–11)  
 2.44–4.86 85 495 21 858 (26) 36.9 (25.8–52.8)  8.1 (5.5–11.9)  
 ≥4.87 86 330 37 153 (43) 81.2 (55.6–118.4)  11.4 (7.1–18.4)  

CI, confidence interval.

The study cohort comprised 312 APR DRGs. The 20 APR DRGs (6% of APR DRGs) with the highest total DOT accounted for 47% of DOT (135 910 days) and 48% of IV acetaminophen costs ($14.2 million). Nineteen of these APR DRGs included a surgical procedure and 1 was a medical diagnosis. Four were neonate related (Table 2).

TABLE 2

IV Acetaminophen Use and Cost for the 20 APR DRGs With the Largest Contributions to DOT in 2019

EncountersUnique PatientsEncounters Receiving IV AcetaminophenDays of IV AcetaminophenDOT per EncounterCost Incurred
APR DRG       
 Appendectomy 20 452 20 429 9958 18 447 1.9 $2 236 511 
 Major small and large  bowel procedure 3701 3281 2714 12 452 4.6 $1 574 878 
 Craniotomy  (nontrauma) 6660 6101 4104 11 093 2.7 $1 365 950 
 Tonsil and  adenoidectomy 19 669 19 603 8679 9629 1.1 $598 447 
 Dorsal and lumbar  fusion procedure 4800 4787 3627 7476 2.1 $1 038 159 
 BMT 1519 1281 852 6899 8.1 $748 025 
 Moderately extensive  procedure 8126 7955 2998 6777 2.3 $690 453 
 Other cardiothoracic  procedure 3720 3694 2612 6131 2.3 $534 194 
 Neonate >2499 g Major  procedure 2370 2370 1288 5843 4.5 $474 640 
 Major repair of heart  anomaly 2357 2338 1809 5570 3.1 $472 814 
 Infectious disease with  OR procedure 2815 2787 1186 5373 4.5 $702 850 
 Other small and large  bowel procedure 2368 2297 1384 5292 3.8 $690 448 
 Tracheostomy with  procedure or ECMO 1434 1427 852 5023 5.9 $476 937 
 Neonate 1500–2499 g  major procedure 1328 1327 765 4765 6.2 $313 903 
 Extensive procedure 2923 2866 1354 4740 3.5 $474 881 
 Neonate <1500 g major  procedure 1388 1386 620 4459 7.2 $366 740 
 Septicemia 9122 8573 1571 4243 2.7 $474 021 
 Neonate>2499 g  Cardiovascular  procedure 2290 2289 1040 4162 4.0 $321 738 
 Cardiac valve  procedure  (noncatheterization) 2192 2175 1600 3978 2.5 $394 759 
 ENT procedure 5937 5657 2547 3558 1.4 $276 515 
Total of top 20 APR DRGs 105 171 102 623 51 560 135 910 — $14 226 862 
Total of all other APR DRGs (n = 292) 761 175 574 874 73 896 152 025 — $15 544 032 
Total across all DRGs 866 346 677 497 125 456 287 935 — $29 770 894 
EncountersUnique PatientsEncounters Receiving IV AcetaminophenDays of IV AcetaminophenDOT per EncounterCost Incurred
APR DRG       
 Appendectomy 20 452 20 429 9958 18 447 1.9 $2 236 511 
 Major small and large  bowel procedure 3701 3281 2714 12 452 4.6 $1 574 878 
 Craniotomy  (nontrauma) 6660 6101 4104 11 093 2.7 $1 365 950 
 Tonsil and  adenoidectomy 19 669 19 603 8679 9629 1.1 $598 447 
 Dorsal and lumbar  fusion procedure 4800 4787 3627 7476 2.1 $1 038 159 
 BMT 1519 1281 852 6899 8.1 $748 025 
 Moderately extensive  procedure 8126 7955 2998 6777 2.3 $690 453 
 Other cardiothoracic  procedure 3720 3694 2612 6131 2.3 $534 194 
 Neonate >2499 g Major  procedure 2370 2370 1288 5843 4.5 $474 640 
 Major repair of heart  anomaly 2357 2338 1809 5570 3.1 $472 814 
 Infectious disease with  OR procedure 2815 2787 1186 5373 4.5 $702 850 
 Other small and large  bowel procedure 2368 2297 1384 5292 3.8 $690 448 
 Tracheostomy with  procedure or ECMO 1434 1427 852 5023 5.9 $476 937 
 Neonate 1500–2499 g  major procedure 1328 1327 765 4765 6.2 $313 903 
 Extensive procedure 2923 2866 1354 4740 3.5 $474 881 
 Neonate <1500 g major  procedure 1388 1386 620 4459 7.2 $366 740 
 Septicemia 9122 8573 1571 4243 2.7 $474 021 
 Neonate>2499 g  Cardiovascular  procedure 2290 2289 1040 4162 4.0 $321 738 
 Cardiac valve  procedure  (noncatheterization) 2192 2175 1600 3978 2.5 $394 759 
 ENT procedure 5937 5657 2547 3558 1.4 $276 515 
Total of top 20 APR DRGs 105 171 102 623 51 560 135 910 — $14 226 862 
Total of all other APR DRGs (n = 292) 761 175 574 874 73 896 152 025 — $15 544 032 
Total across all DRGs 866 346 677 497 125 456 287 935 — $29 770 894 

BMT, bone marrow transplant, ENT, ear nose and throat; OR; operating room. —, not applicable.

Appendectomy had the highest DOT for IV acetaminophen use (18 447 days), with 32% more DOT than that of the second-ranked APR DRG, major small and large bowel procedure (12 452 days). Craniotomy, tonsil and adenoidectomy, dorsal, and lumbar spinal fusion were also in the top quartile in terms of DOT. Appendectomy is an example of an APR DRG with a large volume of treated encounters (n = 9958) with short average duration of therapy (1.9 days per encounter). In contrast, major small and large bowel procedure had fewer treated encounters (n = 2714) but longer average duration of therapy (4.6 days per encounter).

The observed rate of IV acetaminophen use at the hospital-level ranged from <0.1% to 43% across hospitals (Fig 1). Even after accounting for patient demographic and clinical factors associated with IV acetaminophen use, wide variation in adjusted hospital-level use persisted (range <0.1%–31%), which suggests that peer pediatric hospitals are using IV acetaminophen at varying rates in similar populations. Furthermore, 19% of the hospitals (9 PHIS hospitals) use IV acetaminophen in less than 5% of all patient observed and adjusted encounters despite similar clinical populations.

FIGURE 1

Observed and adjusted IV acetaminophen use in inpatient encounters from 48 pediatric hospitals in 2019.

FIGURE 1

Observed and adjusted IV acetaminophen use in inpatient encounters from 48 pediatric hospitals in 2019.

Close modal

In Figure 2 we display boxplots of the distribution of hospital IV acetaminophen use within each of the 20 highest using APR DRGs. In 3 APR DRGs (dorsal and lumbar fusion, major repair of heart anomaly, and cardiac valve procedure [noncatherization]), median hospital IV acetaminophen use was >90%, indicating that IV acetaminophen use is high in these populations at the majority of hospitals. In contrast, in septicemia, the median hospital IV acetaminophen use was 17%, indicating consensus away from use. We also observed wide hospital variation in IV acetaminophen use, with IQRs ranging from 17% for septicemia to 67% for tonsil and adenoidectomy. Fifteen of these APR DRGs had IQR >50%, another indication of lack of consensus.

FIGURE 2

Variation in hospital IV acetaminophen use within the 20 APR DRGs with the largest contributions to DOT in 2019. BMT, bone marrow transplant; ENT, ear nose and throat; OR; operating room.

FIGURE 2

Variation in hospital IV acetaminophen use within the 20 APR DRGs with the largest contributions to DOT in 2019. BMT, bone marrow transplant; ENT, ear nose and throat; OR; operating room.

Close modal

To identify priority populations for reduction of IV acetaminophen use and future standardization, we propose an APR DRG prioritization framework that takes into account the potential magnitude for reduction in use (total DOT) and variation in practice (IQR of use across hospitals). We defined high-priority APR DRGs as those with the greatest contributions to IV acetaminophen use (ie, top quartile in DOT) accompanied by wide variation in IV acetaminophen use (ie, IQR across hospitals >50%). In Figure 3 we illustrate the prioritization framework. Appendectomy is a high contributor to use (18 447 DOT), with wide variation in IV acetaminophen across hospitals (IQR 55%, median 60%), and a large number of encounters (20 452). Another high-priority population is tonsil and adenoidectomy, with a high contribution of use (DOT = 9629), with wide variation across hospitals (IQR 67%, median hospital use 40%) and a large number of encounters (19 669). Appendectomy, tonsil and adenoidectomy, and craniotomy are strong candidates for future reduction and standardization efforts to mitigate excessive IV acetaminophen use and its associated cost.

FIGURE 3

Prioritization framework for IV acetaminophen standardization efforts. DOT versus IQR of hospital use for the high-use APR DRGs. Bubble size indicates number of treated encounters.

FIGURE 3

Prioritization framework for IV acetaminophen standardization efforts. DOT versus IQR of hospital use for the high-use APR DRGs. Bubble size indicates number of treated encounters.

Close modal

The cost associated with IV acetaminophen use was $29.8 million among 866 346 children hospitalized in 2019. We found substantial variation in IV acetaminophen use across the 48 study hospitals, ranging from <0.1% to 31% of all hospital encounters after adjusting for patient factors. Of the 312 diagnostic groups examined, 20 diagnostic groups accounted for 47% of the total use and 48% of the total cost of IV acetaminophen in 2019. Within these 20 high-use diagnosis groups, we found high variability across pediatric hospitals in use of IV acetaminophen for each diagnosis, especially for appendectomy, tonsil and adenoidectomy, and craniotomy.

IV acetaminophen has been widely incorporated into clinical practice across pediatric hospitals despite its high cost and the availability of alternative formulations. One of the clinical applications of IV acetaminophen is as a nonopioid analgesic. Although the initial marketing campaign focused on the opioid-sparing effects, a majority of pediatric studies suggest only a modest clinical benefit of the IV formulation. Authors in a few single-center studies reported small decreases in opioid equivalents when using IV acetaminophen compared with placebo in the neonatal and pediatric populations.8,19,20  However, researchers in other pediatric studies evaluating the opioid-sparing effects of IV acetaminophen compared with enteral or rectal formulations indicated a lack of superiority of IV acetaminophen.10,21,22  The second clinical application of IV acetaminophen is as an antipyretic. In an observational single-center study, IV acetaminophen was compared with oral acetaminophen in the management of fevers. The authors demonstrated patients receiving IV acetaminophen had faster fever descent compared with the oral formulation; however, beyond 4 hours, there was no difference between the 2 groups.23 

In this study, we do not evaluate the opioid-sparing effect of IV acetaminophen, including, but not limited to, the presence of an ileus, length of stay, and total opioids received. The PHIS database documents the presence of opioid charges per day rather than the granular doses received by the patient. In previous studies, researchers using the PHIS database have evaluated opioid exposure as a dichotomous variable.24  Future investigation is needed to understand whether institutions with high use of IV acetaminophen correspond to lower opioid DOT and shorter length of stays.

Despite the limited evidence for enhanced efficacy, with our study, we demonstrated there remains a portion of hospitals that use IV acetaminophen upwards of 2 times the median hospital rate of 15.5% of adjusted encounters. Because the data do not clearly demonstrate a benefit, the high degree of variation is unexplained. We speculate it is due to a lack of consensus on which patient populations warrant use of IV acetaminophen. Given the high price point of the IV formulation and variation in practice, further research is imperative to identify patient populations that benefit from IV acetaminophen as well as from practice standardization to control use. Future research focusing on practice patterns and standardization in appendectomy, tonsil and adenoidectomy, and craniotomy will create a platform for implementation for the remaining high-use DRGs.

With our study, we demonstrated a skewed pattern of use toward 20 diagnosis groups accounting for 47% of the total use and $14.2 million. We further demonstrated that pediatric hospitals use IV acetaminophen at varying rates for each diagnosis. Appendectomy, tonsil and adenoidectomy, and craniotomy are candidate diagnosis to further evaluate hospital factors that contribute to use. Other potential contributors to the hospital variability include presence of IV acetaminophen on hospital formulary, incorporation into order sets, and pediatric hospitals with formulary management systems. In the adult literature, widespread use of IV acetaminophen has been associated with hospital formulary adoption, extending pharmacy approval from 24 to 48 hours of use, and use of postoperative order sets incorporating IV acetaminophen.25  As hospitals aim for provider efficacy, the implementation of order sets in the electronic medical record has increased the prescribing of certain medications and laboratories.26  Future research is needed to define the factors contributing to varying use rates across the PHIS hospitals to inform cost reduction and practice standardization initiatives.

One of the strengths of this study is the large number of pediatric hospitals in the United States that contribute data to the PHIS network. By querying the PHIS database, we were able to evaluate clinical and resource use in pediatric hospitals. Another strength of this study is evaluating hospital IV acetaminophen use across multiple diagnosis groups to understand the depth of variation in practice patterns. A major implication of this study is the need for standardization of IV acetaminophen use. Within a given DRG, hospitals are using IV acetaminophen in vastly different patterns without demonstrated patient benefit.

The results of this study must be considered in the context of certain limitations. We used each hospital’s pharmacy-specific ratio of costs to charges to calculate cost of IV acetaminophen on the basis of billed charges. The $29.7 million incurred by IV acetaminophen use at these 48 pediatric hospitals in 2019 is an estimate of resources expended by the institutions and does not reflect actual costs incurred by the institutions or payments received by the hospitals. The PHIS network’s quality assurance is a collaborative effort between the hospitals and the CHA. Errors in coding and billing are still possible despite the rigorous audits. In addition, we were unable to assess the total doses of IV acetaminophen received by patients, precluding further analysis of doses of IV acetaminophen per encounter. Another limitation is using billing data to account for a patient’s clinical complexity. CMI is used as an indicator for disease severity. CMI is subject to the accuracy of the health provider documentation of the patient and the coder extracting the data.27  Mendez et al demonstrated that CMI’s can be higher for patients who cost more money to care for rather than those with more severe disease.28  A cofounding factor of IV acetaminophen use is the patient’s enteral status. PHIS does not document the enteral status of patients or the enteral practice patterns of the health care institutions. Depending on a patient’s clinical status, preoperative and postoperative surgical procedure, TPN, ECMO, mechanical ventilation, and a complex chronic condition are not contraindications to enteral medications. Finally, PHIS data are limited to the hospitals within the network; we are unable to calculate the entire cost to the health care system.

We observed large variation in IV acetaminophen use across pediatric hospitals and within specific diagnosis groups. The high cost of IV acetaminophen coupled with limited evidence demonstrating superiority to available alternatives support the implementation of practice reduction and standardization efforts. Candidate conditions for such initiatives include appendectomy, tonsil and adenoidectomy, and craniotomy. Identifying specific policies and practices that effectively decrease unnecessary hospital use of IV acetaminophen could help guide initiatives targeting these conditions.

FUNDING: No external funding.

Dr Toomey conceptualized and designed the study and drafted the initial manuscript; Dr Graham conducted the initial analyses and reviewed and revised the manuscript; Drs Randolph and Bourgeois conceptualized and designed the study and critically reviewed the manuscript; and all authors approved the final manuscript as submitted.

Individual participant data are not applicable. All of the data from the database collection during the study will be available immediately following the publication with no end date. The data will be made available on publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to vanessa.toomey@childrens.harvard.edu.

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.