Using Quality Improvement to Implement a Standardized Approach to Neonatal Virus Laura H. Brower, MD,a,b Paria M. Wilson, MD, MEd,b,c,d,e Eileen Murtagh Kurowski, MD, MSc,b,c,f David Haslam, MD,b,g Joshua Courter, PharmD,h Neera Goyal, MD, MSc,a,b,i,j Michelle Durling, MEd,a Samir S. Shah, MD, MSCE,a,b,f,g Amanda Schondelmeyer, MD, MSca,b,f

OBJECTIVES: Neonatal (HSV) are associated with abstract high mortality and long-term morbidity. However, incidence is low and acyclovir, the treatment of choice, carries risk of toxicity. We aimed to increase the percentage of patients 0 to 60 days of age who are tested and treated for Divisions of aHospital Medicine, cPediatric Emergency Medicine, gInfectious , and hPharmacy, Cincinnati HSV in accordance with local guideline recommendations from 40% to 80%. Children’s Hospital Medical Center, Cincinnati, Ohio; b METHODS: This quality improvement project took place at 1 freestanding Department of , College of Medicine, University of Cincinnati, Cincinnati, Ohio; dDivision of Pediatric Emergency children’s hospital. Multiple plan-do-study-act cycles were focused on Medicine, Children’s Hospital of Pittsburgh, University of interventions aimed at key drivers including provider buy-in, guideline Pittsburgh Medical Center, Pittsburgh, Pennsylvania; e fi Department of Pediatrics, School of Medicine, University of availability, and accurate identi cation of high-risk patients. A run chart was Pittsburgh, Pittsburgh, Pennsylvania; iDivision of External used to track the effect of interventions on the percentage managed per Primary Care, Nemours/Alfred I duPont Hospital for Children, Wilmington, Delaware; jDepartment of Pediatrics, guideline recommendations over time by using established rules for Sidney Kimmel Medical College, Thomas Jefferson determining special cause. Pre- and postimplementation acyclovir use was University, Philadelphia, Pennsylvania; and fJames M. compared by using a x2 test. In HSV-positive cases, delayed acyclovir Anderson Center for Health Systems Excellence, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio initiation, defined as .1 day from presentation, was tracked as a balancing measure. Drs Brower, Wilson, and Schondelmeyer conceptualized and designed the study, oversaw RESULTS: The median percentage of patients managed according to guideline improvement activities, and drafted the initial recommendations increased from 40% to 80% within 8 months. Acyclovir manuscript; Drs Murtagh Kurowski, Haslam, Goyal, P , – and Shah participated in the design of the study and use decreased from 26% to 7.9% ( .001) in non high-risk patients but did the design of the interventions for improvement; Ms not change significantly in high-risk patients (73%–83%; P 5 .15). There Durling and Dr Courter participated in the design of were no cases of delayed acyclovir initiation in HSV-positive cases. the study, the design of the interventions for improvement, and provided data support; and all CONCLUSIONS: Point-of-care availability of an evidence-based guideline and authors reviewed and revised the manuscript and interventions targeted at provider engagement improved adherence to a new approved the final manuscript as submitted. guideline for neonatal HSV management and decreased acyclovir use in DOI: https://doi.org/10.1542/peds.2018-0262 non–high-risk . Further study is necessary to confirm the safety of Accepted for publication Apr 23, 2019 these recommendations in other settings. Address correspondence to Amanda Schondelmeyer, MD, MSc, Division of Hospital Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, ML 9016, Cincinnati, OH 45229. E-mail: [email protected] Herpes simplex virus (HSV) is a rare, delayed initiation of acyclovir therapy,4 potentially fatal neonatal with which is associated with a significantly PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). an estimated incidence of 9.6 per higher odds of mortality.5 However, Copyright © 2019 by the American Academy of 100 000 births.1 Initial manifestations of testing and empirically treating Pediatrics neonatal HSV infection vary and often every febrile neonate with acyclovir include nonspecific signs (eg, regardless of symptomatology is not To cite: Brower LH, Wilson PM, Murtagh 6 hypothermia, decreased feeding), cost-effective and may lead to Kurowski E, et al. Using Quality Improvement to making early identification challenging.2, medication-related side effects, Implement a Standardized Approach to Neonatal 3 This variability in presentation can including acute kidney injury (AKI),7–9 Herpes Simplex Virus. Pediatrics. 2019;144(2): e20180262 lead to delayed recognition of HSV and and extravasation injury.10,11

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 144, number 2, August 2019:e20180262 QUALITY REPORT The recommended workup by the medicine, hospital medicine (HM), status because most infants American Academy of Pediatrics for infectious diseases, , and presenting with nonspecific suspected neonatal HSV includes pharmacy divisions. We assessed symptoms and normal CSF polymerase chain reaction (PCR) local practice patterns16 and parameters will not have HSV testing of surface swabs (mouth, conducted a structured literature .6,26 nasopharynx, conjunctivae, rectum, search with a biomedical librarian. vesicles), serum and cerebrospinal The team reviewed the literature for Patient Population fluid (CSF), and blood for alanine risk factors, testing strategies, and We included patients 0 to 60 days of aminotransferase.12 However, outside treatment of neonatal HSV using age on the basis of local physician the immediate ,13 a structured evidence appraisal testing and treatment patterns for there is little guidance for clinicians tool.17 When evidence was HSV. Birth hospitalizations or on initiating testing and therapy for insufficient, the team developed interhospital transfers after birth neonatal HSV. consensus-based recommendations, were excluded. incorporating input from stakeholder In 2014, we developed an divisions. The resulting evidence- institutional guideline for neonatal Interventions informed and consensus-based HSV. In our approach, all neonates guideline for neonatal HSV We used the Model for younger than 22 days being evaluated 33 management was focused on Improvement to determine the for serious bacterial infection (SBI) stratifying infants into high- and effects of interventions on guideline have CSF-HSV-PCR testing performed, non–high-risk groups on the basis of adherence. We used sequential small but only those presenting with high- history, physical examination, and CSF tests of change, or plan-do-study-act risk features and/or abnormal CSF cycles,33 of interventions targeting 14 parameters (Fig 1). parameters (Fig 1) undergo more identified key drivers (Fig 2). 12,15 extensive testing and receive Our guideline suggests evaluation 16 empirical acyclovir therapy. Our according to published Care Provider Education objective of this study was to use 12 recommendations and empirical Physicians and/or Nurse Practitioners quality improvement (QI) treatment with acyclovir pending test methodology to increase local results for infants with higher-risk Study team members (L.H.B., A.S., guideline adherence from 40% to features concerning for HSV.18–28 P.M.W.) conducted presentations for 80% within 8 months. Researchers do report that infants pediatric providers from pertinent with isolated central nervous system divisions (emergency medicine, HM, (CNS) disease can rarely present with infectious diseases, neonatology) at METHODS nonspecific symptoms and without educational conferences and division 25–27 meetings. In these presentations the Setting CSF pleocytosis. Considering the test characteristics of the HSV CSF guideline rationale, evidence for risk Our QI project took place at a .650- – PCR,28 30 we felt that non–high-risk factors, and the multidisciplinary bed freestanding children’s hospital infants within the age range when consensus process for guideline and its 40-bed satellite location with perinatally acquired HSV most development were summarized. We ∼93 000 emergency department (ED) , 24–26, also implemented annual resident ∼ commonly presents ( 22 days) visits and 35 000 admissions 31,32 didactic updates because of yearly could be screened for CNS annually. The ED and pediatric units trainee turnover. disease with HSV CSF PCR only. are staffed by pediatric residents and Although infants can present nurse practitioners supervised by .21 days of age, they do so with such Nursing fellow and attending physicians and insufficient frequency that we felt the use a common electronic health Because of nursing questions risks of false-positive testing record (EHR). There is a PCR regarding laboratory evaluation, we outweighed the benefit of a broad laboratory staffed Monday through expanded our educational initiatives. screening approach in this subset of Saturday, with on-call availability In the ED, a core group of nurses older infants. Therefore, we Sundays. PCR tests are run once daily serve as care leaders for patients recommended that infants 22 to and by request, and the median receiving more intensive care. 28 days have CSF held and no testing turnaround time is 15 hours Because of their expertise and (interquartile range: 9–20). performed. Our guideline consistent ED presence, education recommends not administering about the HSV care pathway was Before the start of our QI project, acyclovir empirically for these infants provided to these core nurses at their we convened a multidisciplinary and instead awaiting a positive HSV educational conferences by a study stakeholder team from the emergency test result or changes in clinical team member (P.M.W), focusing on

Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 BROWER et al FIGURE 1 Guideline algorithm for risk assessment, testing, and treatment of neonatal HSV. a This list is not inclusive of all risk factors for neonatal HSV disease. b Disseminated HSV disease can present with respiratory distress. c While awaiting results of CSF cell counts, differential, and Gram-stain. d Includes but not limited to vesicles, ulcers or pustular lesions, local pain, itching, tingling, burning, pruritus, dysuria, local lymphadenopathy, and systemic symptoms including fever, malaise, and headache. e Preterm infants are at higher risk for hypothermia and apnea related to non-HSV viral infections or environmental factors. Consider discussing workup of these patients with neonatal intensive care. WBC, white blood cell. nursing care (eg, components of This allowed providers to access the 0–28 days and high risk for HSV, (2) complete HSV laboratory evaluation). guideline directly from their 0–21 days and non–high risk for HSV, patient’s chart. (3) 22–28 days and non–high risk for Guideline Availability HSV, and (4) $29 days. Text within For point-of-care guideline ED Order Sets the order set supported clinical availability, copies of the flowchart We worked with EHR specialists to management according to guideline were posted in the resident and HM develop higher-reliability recommendations, including high-risk provider workrooms. In the ED, interventions to assist providers in HSV features that were based on a slideshow highlighting key following guideline history, physical examination, and CSF guideline components was presented recommendations. A new order set results. In each subgroup, laboratory on workspace screens. The guideline for the evaluation of serious infection tests and nursing orders were was also added to an ED-specific EHR in infants was developed with preselected, forcing providers to opt system that houses clinical guidelines, subgroups that were based on the out of guideline recommendations. accessible from the ED EHR navigator. ’s age and HSV risk status: (1) Medications were not preselected, but

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 144, number 2, August 2019 3 for serious infection who were tested and treated for HSV in accordance with guideline recommendations. We measured percentage adherence for groups of 10 consecutive eligible patients to account for seasonal variation in volume and provide more opportunities for learning. We also tracked the number of patients at each risk level (high, nonhigh, and unable to be determined). Secondary outcomes included (1) percentage of patients treated with $1 dose of acyclovir by risk level, (2) percentage FIGURE 2 of high-risk patients with a complete Key driver diagram. APP, advanced practice provider. laboratory evaluation for HSV,12 and (3) number of non–guideline- order set text encouraged guideline- when patients #60 days of age had recommended HSV PCR tests per adherent acyclovir use (Fig 3). a CSF or blood culture ordered. patient. Patients whose risk level was unclear were excluded from the Study of the Intervention Structured EHR review was secondary outcome analysis but were performed by using the Research treated as high risk for the primary Baseline data included patients from Electronic Data Capture tool34 for outcome measure. As balancing a 6-month period (January to June patient age, sex, , measures, we followed median length 2014) who were retrospectively presence of complex chronic of stay (LOS) for admitted patients identified on the basis of age 35 conditions, and ICU stay. For (overall and by risk level), cases of #60 days at presentation and guideline adherence, the HSV risk AKI,36 delayed acyclovir initiation for laboratory orders (CSF and/or blood level (high or nonhigh; Fig 1) was HSV-positive cases, defined as .1day culture). We chose this time to assigned by the study team (L.H.B., from presentation,5 and deaths from represent preguideline clinical M.D.) using clinical presentation, HSV infection. practice when providers would not physical examination, and CSF data. have been aware of any guideline Guideline adherence was then development activities that could Analysis determined by testing and acyclovir have biased their practice. During the A run chart was used to analyze our use as a bundled measure. intervention period, a real-time EHR- primary outcome measure and integrated decision support system established rules were used to was used to identify potentially Measures identify special-cause variation.37–41 eligible patients. This decision The primary outcome measure was Age at presentation, pre- and support system generated real-time the percentage of patients, 0 to postimplementation LOS, and e-mail alerts to study team members 60 days of age, undergoing evaluation non–guideline-recommended PCR

FIGURE 3 ED order set for the evaluation of serious infection in infants. CCHMC, Cincinnati Children’s Hospital Medical Center; GGT, gamma-glutamyl transferase; WBC, white blood cell.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 4 BROWER et al tests per patient were compared by TABLE 1 Description of Study Population using a Wilcoxon rank-sum test. Characteristics Baseline (n 5 Implementation (n 5 P Clinical and/or demographic 160) 1120) characteristics were compared by Average age at presentation, d, mean 6 SD 26.4 6 14.9 30.6 6 16.1a .002 using Fisher’s exact test. Pre- and Male sex, n (%) 99 (62) 616 (55) .11 postimplementation acyclovir use Gestational age ,34 wk,b n (%) 5 (3.1) 21 (1.9) .36 and complete HSV evaluations for Complex chronic conditions, n (%) Neurologic 2 (1.3) 11 (1.0) .67 high-risk patients were compared by Cardiac 1 (0.6) 8 (0.7) 1.00 2 using a x test. Descriptive statistics Genitourinary and/or renal — 9 (0.8) .61 were used for cases of AKI and, in Genetic 1 (0.6) 9 (0.8) 1.00 HSV cases, to asses death and timing Gastrointestinal 1 (0.6) 3 (0.3) .41 — of acyclovir. Pulmonary 2 (0.2) 1.00 Other 1 (0.6) 6 (0.5) 1.00 a Ethical Considerations ICU stay, n (%) 11 (6.9) 155 (14) .01 HSV exposure, n (%) This study was reviewed by the local Maternal HSV symptoms 1 (0.6) 20 (1.8) .50 institutional review board and Other known HSV contacts — 23 (2.1) .10 determined to be exempt. Symptoms and/or PE findings at presentation, n (%) Fever $38°C 100 (63) 765 (68) .15 RESULTS Hypothermia ,36°Cc 10 (6.3) 85 (7.6) .63 Ill appearance/poor perfusion 17 (11) 103 (9.2) .56 There were 160 eligible encounters Respiratory symptoms 67 (42) 479 (43) .87 during the baseline period and 1120 Difficulty breathing 9 (5.6) 169 (15)a .001 encounters during the Apneac 9 (5.6) 62 (5.5) 1.00 a implementation period. Forty-two GI symptoms 83 (52) 480 (43) .03 Poor feeding 65 (41) 345 (31)a .01 patients had 2 separate encounters Vomiting 26 (16) 179 (16) .91 during the study period. Clinical Neurologic symptoms 39 (24) 489 (44)a ,.001 characteristics of included encounters 5 (3.1) 52 (4.6) .54 are presented in Table 1. Patients in Altered mental status 11 (6.9) 60 (5.4) .46 the implementation period were Abnormal neurologic examination 5 (3.1) 25 (2.2) .41 Skin and soft-tissue symptoms 19 (12) 119 (11) .59 older at presentation, and a higher Vesicular or petechial rash 6 (3.8) 63 (5.6) .45 percentage had ICU stays, difficulty Poorly healing scalp electrode site — 3 (0.3) 1.00 breathing, and neurologic symptoms. HEENT symptoms 7 (4.4) 60 (5.4) .71 A higher percentage of baseline Genitourinary symptoms — 1 (0.09) 1.00 patients had gastrointestinal Hematologic symptoms 1 (0.6) 6 (0.5) 1.00 Excessive bleeding — 1 (0.09) 1.00 symptoms and poor feeding. A total of 275 patients (19%) were at high risk Reported P values are 2-sided. GI, gastrointestinal; HEENT, head, ear, eye, nose, and throat; PE, physical examination. —, not applicable. for HSV. A small number of patients a P value ,.05. Wilcoxon rank-sum test was used for age at presentation. Fisher’s exact test was used for all other could not have their risk level variables. determined because they were not at b For 4 infants, the gestational age at birth was not documented. c In infants .34 wk gestation. high risk for HSV by history and physical examination but did not have CSF cell counts; this was often implementation of the ED order set in September 2016, we have because of the inability to obtain modifications and availability of the sustained at 80% guideline adequate CSF volume (n 5 35; 67%) guideline in workspaces and the ED adherence for 9 months. or lumbar puncture (n 5 12; 23%) EHR clinical guideline system. (Table 2). Secondary outcome measures are The percentage of neonates 0 to In July 2016, we experienced displayed in Table 2. Acyclovir use 60 days of age undergoing evaluation a downward shift to 70%, coinciding significantly decreased more than for serious infection who were tested with yearly resident changeover. In threefold in non–high-risk patients. and treated for neonatal HSV in response, we implemented There was no statistically significant accordance with local guideline a recurring educational intervention change for high-risk patients. The recommendations increased from targeted toward times of high trainee percentage of high-risk patients 40% to 80% within 8 months (Fig 4). turnover. In addition, we provided undergoing complete HSV evaluation The initial shift to our goal of 80% further education to the core group of increased significantly. For non–high- occurred in March 2016 after the ED nurses. Since shifting back to goal risk patients, PCR tests per patient

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 144, number 2, August 2019 5 TABLE 2 Secondary Outcome Measures and LOS guideline-adherent testing and Baseline (n 5 160) Implementation treatment, 37% received acyclovir, (n 5 1120) and 57% of those ,22 days of age did High risk for HSV, n (%) 37 (28) 238 (21) not have CSF HSV testing. For our Acyclovir 27 (73) 197 (83) balancing measures, median LOS did Complete evaluation 3 (8.1) 98 (41)a not change (overall or by risk level; – Non high risk for HSV, n (%) 119 (74) 834 (74) Table 2). There were 2 cases of AKI, Acyclovir, n (%) 31 (26) 66 (7.9)a PCR tests per patient,b ratio 0.33 0.16a both during implementation in Unable to determine risk level,c n (%) 4 (3%) 48 (4.3%) infants receiving acyclovir. There LOS in d, median (IQR) 1.91 (1.70, 2.92) 1.91 (1.65, 3.05) were 15 HSV disease cases (1 during High risk for HSV 2.00 (1.72, 2.85) 2.26 (1.80,4.34) baseline) and no deaths. There were – Non high risk for HSV 1.90 (1.69, 2.94) 1.83 (1.62, 2.68) no missed HSV cases after guideline IQR, interquartile range. implementation. a P value ,.05. x2 test was used for acyclovir use and complete evaluation. Wilcoxon rank-sum test was used for PCR tests per patient and LOS. b PCR tests were only included if they were nonrecommended per the guideline. c Non–high risk was based on history and physical examination but unable to obtain CSF cell counts. DISCUSSION With interventions that were focused decreased significantly. Among adherence over the last year of 92% on provider buy-in and guideline non–high-risk patients, guideline in patients $29 days old vs 69% in availability with just-in-time adherence was higher in patients patients 0 to 28 days old. Of the reminders at point of care, we $29 days old, with an overall patients 0 to 28 days of age without successfully increased the percentage

FIGURE 4 Run chart revealing the percentage of patients receiving guideline-adherent management. a The date range is detailed for every other data point.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 6 BROWER et al of infants tested and treated for incomplete adherence may represent they use different age ranges and do neonatal HSV in accordance with local ongoing provider concern about not recommend empirical testing guideline recommendations from testing without empirically treating without treatment. Like our study, 40% to 80% within 8 months and despite efforts to educate providers they demonstrated decreased HSV have sustained that improvement for about the potential for isolated CNS CSF testing for those at non–high risk 9 months. Thus, we optimized disease with normal CSF cell counts of HSV; however, they did not have laboratory testing and acyclovir use, and the opportunity for rapid local a statistically significant change in including increasing appropriate PCR testing to prevent significant PCR testing in patients at higher risk testing of high-risk infants and delays in acyclovir administration, or in acyclovir use. Our study differs decreasing acyclovir administration noting that before our guideline, in the use of QI methodology to to infants without high-risk features, many of these infants would have describe interventions and without adversely affecting LOS. received no evaluation for HSV. In demonstrate adherence over time. Additionally, our interventions did high-risk infants, we continue to work Other approaches to the management not lead to delays in acyclovir on obtaining complete evaluations, of neonatal HSV have been described. initiation for infants with HSV emphasizing surface and serum PCR Long et al25 described their disease. testing. Because approximately one- experience with universal testing and third of infants with disseminated empirical acyclovir for all neonates Our interventions can be divided into disease have no CNS involvement,48 ,21 days old, detailing cases of 2 main groups. The first group testing beyond the CSF is critical for diagnosed HSV disease. Byington involved education of frontline diagnosis in these infants. et al52 recommend testing and providers and ensuring guideline treating for HSV in infants #42 days accessibility at the point of care. Even with continued challenges, the old with vesicular rash, , or These low-reliability42 interventions decrease in acyclovir initiation for abnormal CSF and to consider HSV if were critical to obtaining initial buy- non–high-risk patients has potential septic. They have reported an in. However, we did not achieve benefits. In older children, even short increase in evidence-based care but sustained change until adopting acyclovir courses have been shown to – without specific reference to HSV. higher-reliability interventions, have nephrotoxic side effects.7 9 Further evidence establishing the including changing the ED EHR so Although the AKI prevalence among safety and efficacy of these that providers had to opt out of infants receiving short courses of approaches will be necessary, following recommendations and acyclovir is unknown, it is reasonable although it will require multicenter adding just-in-time education. We to extrapolate potential for harm on studies given the low incidence of also benefited from our strong local the basis of evidence in older neonatal HSV. improvement culture43 and history of children. Severe extravasation injury standardization work.44–47 from acyclovir’s alkaline pH is also Several features of our local context, a risk,10,49,50 with particular concern We continue to see variation in data collection, and interventions in neonates because of their more overall adherence, which we may limit generalizability. We flexible subcutaneous tissues and hypothesize is related to the lower acknowledge that the fragile veins.11 These risks highlight reliability of educational recommendation to send CSF testing the importance of appropriately interventions in changing behavior,42 without empirical treatment of identifying those infants at non–high inconsistent order set use in our ED, a subset of non–high-risk infants risk of HSV in whom acyclovir and provider concerns about differs from existing approaches. This initiation can be safely avoided. recommendations for specific decision was intended to balance subgroups of infants. In non–high- Our study differs from previous work negative consequences of acyclovir risk infants ,22 days old, our in our approach of risk stratification therapy and rarity of disease with approach recommends a CSF PCR for neonatal HSV but confirms the normal CSF findings while still without other testing or empirical findings from other studies revealing permitting a broad testing approach acyclovir because of case series of that care may be safely standardized to miss as few cases as possible. infants with early isolated CNS in this population. Ahmad et al51 Additionally, our PCR turnaround disease who present with nonspecific described the development and time is ,24 hours,5 minimizing symptoms and normal CSF indices.25, outcomes of a local guideline for the acyclovir delay for infants who do not 27 For this population, there was management of neonatal HSV. Their receive empirical acyclovir who may lower adherence compared with approach recommended testing and have isolated CNS disease with older non–high-risk infants, with empirically treating for HSV on the normal CSF parameters. Further some receiving acyclovir and some basis of age, presence of HSV risk research is necessary to determine if not undergoing CSF testing. This factors, and CSF results; however, our guideline recommendation to

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 144, number 2, August 2019 7 hold acyclovir treatment may safely between pre- and postintervention delayed acyclovir initiation and be spread to other settings with adherence. Given the previous lack of missed cases of HSV to monitor the variable HSV PCR turnaround time. standardization, we do not believe safety of guideline recommendations. Our work is also limited by our there would be a substantive Although the implementation targeted patient population, which difference in our findings. Finally, strategies used in this QI work are primarily included young infants with because our data were obtained easily replicable, further multicenter perinatally acquired HSV. The through EHR review, the potential work is necessary to establish the guideline recommendations are not for misclassification of patients’ safety of these guidelines in other necessarily applicable to cases of HSV risk, presenting symptoms and settings. in older infants, although these are physical findings, and HSV exposure predominantly acquired outside of history existed. We attempted to ACKNOWLEDGMENTS the perinatal period and present with mitigate this bias through using apparent symptoms (eg, rash).12,15 a standard extraction form and We thank Dr Mark Clee and Julianne Finally, our process changes are minimizing the number of trained Haney for their assistance with the limited in their continued reviewers. abstraction of data. dependence on individual providers to follow guideline recommendations. We attempted to mitigate this by CONCLUSIONS ABBREVIATIONS including higher-reliability tools in We improved adherence to AKI: acute kidney injury our process, such as changes to the a local neonatal HSV guideline CNS: central nervous system EHR order sets. through education, point-of-care CSF: cerebrospinal fluid We used different methods to identify guideline availability, and EHR ED: emergency department patients in the baseline versus changes. Our process improvement EHR: electronic health record intervention periods. Therefore, the has remained at goal for 9 months, HM: hospital medicine preintervention cohort may with plans for ongoing education of HSV: herpes simplex virus incompletely represent the spectrum care providers to sustain process LOS: length of stay of patients for whom this guideline improvement. Because of the PCR: polymerase chain reaction applies. It is unclear how the different potential changing epidemiology of QI: quality improvement methods of identification would affect neonatal HSV,53,54 we will continue to SBI: serious bacterial infection the magnitude of the difference follow patient outcomes, including

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported by a grant from The Gerber Foundation. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

REFERENCES 1. Flagg EW, Weinstock H. Incidence of empiric use of acyclovir by Canadian 7. Schreiber R, Wolpin J, Koren G. neonatal herpes simplex virus pediatric emergency physicians in Determinants of -induced infections in the United States, 2006. febrile neonates. Pediatr Emerg Care. nephrotoxicity in children. Paediatr Pediatrics. 2011;127(1). Available at: 2013;29(3):273–278 Drugs. 2008;10(2):135–139 www.pediatrics.org/cgi/content/full/ 5. Shah SS, Aronson PL, Mohamad Z, Lorch 127/1/e1 8. Jones CA, Walker KS, Badawi N. Antiviral SA. Delayed acyclovir therapy and death agents for treatment of herpes simplex 2. James SH, Kimberlin DW. Neonatal among neonates with herpes simplex virus infection in neonates. Cochrane herpes simplex virus infection. Infect virus infection. Pediatrics. 2011;128(6): Database Syst Rev. 2009; (3):CD004206 Dis Clin North Am. 2015;29(3):391–400 1153–1160 9. Rao S, Abzug MJ, Carosone-Link P, et al. 3. Curfman AL, Glissmeyer EW, Ahmad FA, 6. Caviness AC, Demmler GJ, Swint JM, et al. Initial presentation of neonatal Intravenous acyclovir and renal Cantor SB. Cost-effectiveness dysfunction in children: a matched case herpes simplex virus infection. analysis of herpes simplex – control study. J Pediatr. 2015;166(6): J Pediatr. 2016;172:121 126.e1 virus testing and treatment 1462–1468.e1–e4 4. Benidir A, Lim R, Salvadori M, Sangha G, strategies in febrile neonates. Arch Poonai N. Current practice patterns Pediatr Adolesc Med. 2008;162(7): 10. Le A, Patel S. Extravasation of regarding diagnostic investigations and 665–674 noncytotoxic drugs: a review of the

Downloaded from www.aappublications.org/news by guest on September 30, 2021 8 BROWER et al literature. Ann Pharmacother. 2014; 20. Brown ZA, Benedetti J, Ashley R, et al. 30. Tebas P, Nease RF, Storch GA. Use of the 48(7):870–886 Neonatal herpes simplex virus infection polymerase chain reaction in the in relation to asymptomatic maternal diagnosis of herpes simplex 11. Paquette V, McGloin R, Northway T, infection at the time of labor. N Engl : a decision analysis model. Dezorzi P, Singh A, Carr R. Describing J Med. 1991;324(18):1247–1252 Am J Med. 1998;105(4):287–295 intravenous extravasation in children (DIVE study). Can J Hosp Pharm. 2011; 21. Brown ZA, Wald A, Morrow RA, Selke S, 31. Batra D, Davies P, Manktelow BN, Smith 64(5):340–345 Zeh J, Corey L. Effect of serologic status C. The incidence and presentation of and cesarean delivery on transmission neonatal herpes in a single UK tertiary 12. American Academy of Pediatrics. rates of herpes simplex virus from centre, 2006-2013. Arch Dis Child. 2014; Herpes simplex. In: Kimberlin DW, Long mother to infant. JAMA. 2003;289(2): 99(10):916–921 SS, Brady MT, Jackson MA, eds. Red 203–209 Book 2018: Report of the Committee on 32. Cruz AT, Freedman SB, Kulik DM, et al; Infectious Diseases. 30th ed. Elk Grove 22. O’Riordan DP, Golden WC, Aucott SW. HSV Study Group of the Pediatric Village, IL: American Academy of Herpes simplex virus infections in Emergency Medicine Collaborative Pediatrics; 2018:437–449 preterm infants. Pediatrics. 2006; Research Committee. Herpes simplex 118(6). Available at: www.pediatrics. virus infection in infants undergoing 13. Kimberlin DW, Baley J; Committee on org/cgi/content/full/118/6/e1612 meningitis evaluation. Pediatrics. 2018; Infectious Diseases; Committee on 141(2):e20171688 Fetus and Newborn. Guidance on 23. Wolfert SI, de Jong EP, Vossen AC, et al. management of asymptomatic Diagnostic and therapeutic 33. Langley GJ, Moen RD, Nolan KM, Nolan neonates born to women with active management for suspected neonatal TW, Norman CL, Provost LP. The lesions. Pediatrics. 2013; herpes simplex virus infection. J Clin Improvement Guide: A Practical 131(2):383–386 Virol. 2011;51(1):8–11 Approach to Enhancing Organizational Performance. 2nd ed. San Francisco, 14. Kestenbaum LA, Ebberson J, Zorc JJ, 24. Kimberlin DW, Lin CY, Jacobs RF, et al; CA: Jossey-Bass; 2009 Hodinka RL, Shah SS. Defining National Institute of Allergy and cerebrospinal fluid white blood cell Infectious Diseases Collaborative 34. Harris PA, Taylor R, Thielke R, Payne J, count reference values in neonates and Antiviral Study Group. Natural history of Gonzalez N, Conde JG. Research young infants. Pediatrics. 2010;125(2): neonatal herpes simplex virus electronic data capture (REDCap-- 257–264 infections in the acyclovir era. a metadata-driven methodology and Pediatrics. 2001;108(2):223–229 workflow process for providing 15. American Academy of Pediatrics. translational research informatics Herpes simplex. In: Kimberlin DW, Brady 25. Long SS, Pool TE, Vodzak J, Daskalaki I, support. J Biomed Inform. 2009;42(2): MT, Jackson MA, Long SS, eds. Red Book Gould JM. Herpes simplex virus 377–381 2015: Report of the Committee on infection in young infants during 2 Infectious Diseases. 30th ed. Elk Grove decades of empiric acyclovir therapy. 35. Feudtner C, Hays RM, Haynes G, Geyer Village, IL: American Academy of Pediatr Infect Dis J. 2011;30(7):556–561 JR, Neff JM, Koepsell TD. Deaths Pediatrics; 2015:432–445 attributed to pediatric complex chronic 26. Caviness AC, Demmler GJ, Almendarez Y, conditions: national trends and 16. Brower L, Schondelmeyer A, Wilson P, Selwyn BJ. The prevalence of neonatal implications for supportive care Shah SS. Testing and empiric treatment herpes simplex virus infection services. Pediatrics. 2001;107(6). for neonatal herpes simplex virus: compared with serious bacterial illness Available at: www.pediatrics.org/cgi/ challenges and opportunities for in hospitalized neonates. J Pediatr. content/full/107/6/E99 improving the value of care. Hosp 2008;153(2):164–169 Pediatr. 2016;6(2):108–111 36. Selewski DT, Charlton JR, Jetton JG, 27. Kotzbauer D, Andresen D, Doelling N, et al. Neonatal acute kidney injury. 17. Clark E, Burkett K, Stanko-Lopp D. Let Shore S. Clinical and laboratory Pediatrics. 2015;136(2). Available at: Evidence Guide Every New Decision characteristics of central nervous www.pediatrics.org/cgi/content/full/ (LEGEND): an evidence evaluation system herpes simplex virus infection 136/2/e463 system for point-of-care clinicians and in neonates and young infants. Pediatr guideline development teams. J Eval Infect Dis J. 2014;33(11):1187–1189 37. Carey RG. How do you know that your Clin Pract. 2009;15(6):1054–1060 care is improving? Part I: basic 28. Pinninti SG, Kimberlin DW. Neonatal concepts in statistical thinking. J Ambul 18. Bekhof J, Reitsma JB, Kok JH, Van herpes simplex virus infections. Pediatr Care Manage. 2002;25(1):80–87 Straaten IH. Clinical signs to identify Clin North Am. 2013;60(2):351–365 late-onset in preterm infants. 38. Provost LP, Murray SK. The Health Care 29. Madhavan HN, Priya K, Anand AR, Eur J Pediatr. 2013;172(4):501–508 Data Guide: Learning From Data for Therese KL. Detection of herpes simplex Improvement. 1st ed. San Francisco, CA: 19. Caviness AC, Demmler GJ, Selwyn BJ. virus (HSV) genome using polymerase Jossey-Bass; 2011 Clinical and laboratory features of chain reaction (PCR) in clinical samples neonatal herpes simplex virus infection: comparison of PCR with standard 39. Benneyan JC. Use and interpretation of a case-control study. Pediatr Infect Dis laboratory methods for the detection of statistical quality control charts. Int J. 2008;27(5):425–430 HSV. J Clin Virol. 1999;14(2):145–151 J Qual Health Care. 1998;10(1):69–73

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 144, number 2, August 2019 9 40. Benneyan JC. Statistical quality control a rapid cycle improvement project. in humans. Antimicrob Agents methods in infection control and BMJ Qual Saf. 2014;23(6):499–507 Chemother. 1982;21(3):393–398 hospital epidemiology, part I: 45. Parker MW, Schaffzin JK, Lo Vecchio A, 50. De Souza BA, Shibu M. Painless introduction and basic theory. Infect et al. Rapid adoption of Lactobacillus acyclovir extravasation injury in Control Hosp Epidemiol. 1998;19(3): rhamnosus GG for acute a diabetic. Br J Plast Surg. 2002;55(3): 194–214 . Pediatrics. 2013; 264 41. Benneyan JC. Statistical quality control 131(suppl 1):S96–S102 methods in infection control and 51. Ahmad FA, Storch GA, Miller AS. Impact hospital epidemiology, part II: chart 46. Ambroggio L, Thomson J, Murtagh of an institutional guideline on the care use, statistical properties, and Kurowski E, et al. Quality improvement of neonates at risk for herpes simplex research issues. Infect Control Hosp methods increase appropriate virus in the emergency department. – Epidemiol. 1998;19(4):265–283 antibiotic prescribing for childhood Pediatr Emerg Care. 2017;33(6):396 401 pneumonia. Pediatrics. 2013;131(5). 52. Byington CL, Reynolds CC, Korgenski K, 42. Nolan TRR, Haraden C, GriffinFA. Available at: www.pediatrics.org/cgi/ et al. Costs and infant outcomes after Improving the Reliability of Health Care. content/full/131/5/e1623 IHI Innovation Series White Paper. implementation of a care process Boston, MA: Institute for Healthcare 47. Murtagh Kurowski E, Shah SS, Thomson model for febrile infants. Pediatrics. Improvement; 2004. Available at: www.i J, et al. Improvement methodology 2012;130(1). Available at: www. hi.org/resources/Pages/IHIWhitePape increases guideline recommended pediatrics.org/cgi/content/full/130/1/ rs/ImprovingtheReliabilityofHealthCa blood cultures in children with e16 pneumonia. Pediatrics. 2015;135(4). re.aspx. Accessed December 30, 2018 53. Bradley H, Markowitz LE, Gibson T, Available at: www.pediatrics.org/cgi/ ’ McQuillan GM. Seroprevalence of 43. Cincinnati Childrens Hospital Medical content/full/135/4/e1052 Center. Rapid Evidence Adoption to herpes simplex virus types 1 and 2-- improve Child Health (REACH). Available 48. James SH, Kimberlin DW. Neonatal United States, 1999-2010. J Infect Dis. at: https://www.cincinnatichildrens.org/ herpes simplex virus infection: 2014;209(3):325–333 epidemiology and treatment. Clin service/j/anderson-center/evidence- 54. Roberts CM, Pfister JR, Spear SJ. Perinatol. 2015;42(1):47–59, viii based-care/reach. Accessed December Increasing proportion of herpes 30, 2018 49. Laskin OL, Longstreth JA, Saral R, de simplex virus type 1 as a cause of 44. Brady PW, Brinkman WB, Simmons JM, Miranda P, Keeney R, Lietman PS. genital herpes infection in college et al. Oral antibiotics at discharge for Pharmacokinetics and tolerance of students. Sex Transm Dis. 2003;30(10): children with acute osteomyelitis: acyclovir, a new anti-herpesvirus agent, 797–800

Downloaded from www.aappublications.org/news by guest on September 30, 2021 10 BROWER et al Using Quality Improvement to Implement a Standardized Approach to Neonatal Herpes Simplex Virus Laura H. Brower, Paria M. Wilson, Eileen Murtagh Kurowski, David Haslam, Joshua Courter, Neera Goyal, Michelle Durling, Samir S. Shah and Amanda Schondelmeyer Pediatrics 2019;144; DOI: 10.1542/peds.2018-0262 originally published online July 25, 2019;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/144/2/e20180262 References This article cites 48 articles, 15 of which you can access for free at: http://pediatrics.aappublications.org/content/144/2/e20180262#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Administration/Practice Management http://www.aappublications.org/cgi/collection/administration:practic e_management_sub Quality Improvement http://www.aappublications.org/cgi/collection/quality_improvement_ sub Hospital Medicine http://www.aappublications.org/cgi/collection/hospital_medicine_su b Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 30, 2021 Using Quality Improvement to Implement a Standardized Approach to Neonatal Herpes Simplex Virus Laura H. Brower, Paria M. Wilson, Eileen Murtagh Kurowski, David Haslam, Joshua Courter, Neera Goyal, Michelle Durling, Samir S. Shah and Amanda Schondelmeyer Pediatrics 2019;144; DOI: 10.1542/peds.2018-0262 originally published online July 25, 2019;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/144/2/e20180262

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2019 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on September 30, 2021