Clinical pathway implementation for adult sickle cell vaso-occlusive crises: Impact on healthcare utilization, opioid prescribing, and costs

Abstract

BACKGROUND:

Vaso-occlusive crisis (VOC) is the leading cause of emergency department (ED) visits and hospitalization in sickle cell disease (SCD). Standardized clinical pathways may improve care quality and reduce healthcare utilization, yet regional evidence from Saudi Arabia remains limited.

OBJECTIVES:

To evaluate the clinical and economic impact of a multidisciplinary clinical pathway on VOC management, opioid prescribing, and direct healthcare costs.

DESIGN:

Retrospective before-and-after cohort study

SETTING:

Single-center, 500-bed tertiary referral hospital in Jeddah, Saudi Arabia

PATIENTS AND METHODS:

Adults (≥12 years) with confirmed SCD (HbSS, HbSC, or HbS/β-thalassemia) presenting with isolated VOC were included. Outcomes were compared across two consecutive 12-month periods before (May 2016–April 2017) and after (May 2017–April 2018) pathway implementation.

MAIN OUTCOME MEASURES:

Annual ED visits, hospital admissions, 7-day readmission rate, opioid consumption, length of stay, and direct cost savings.

SAMPLE SIZE:

316 unique patients pre-implementation and 374 post-implementation.

RESULTS:

VOC-related ED visits decreased by 69.7% (14,273 vs. 4,319; P<.001), hospital admissions by 32.9% (520 vs. 349; P<.001), and 7-day readmissions by 69.5% (151 vs. 46; P<.001); the readmission rate fell from 29.1% to 13.2%. Median length of stay decreased from 11.0 to 4.3 days. Meperidine and tramadol utilization declined significantly, whereas morphine use increased by 41.2%. When standardized to oral morphine milligram equivalents, total opioid burden nonetheless decreased by 21.8% overall (33.9% per patient-year). Annual direct cost savings totaled 410 709 Saudi Riyals.

CONCLUSIONS:

Implementation of a multidisciplinary VOC clinical pathway was associated with substantial reductions in healthcare utilization, hospital stay, readmissions, and direct costs, while promoting evidence-based opioid prescribing in adults with SCD.

LIMITATIONS:

Single-center, uncontrolled before-and-after design without adjustment for genotype imbalance between cohorts; incomplete pathway adherence in some clinical areas; patient-reported outcomes were not collected.

INTRODUCTION

Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy caused by a point mutation in the β-globin gene that results in the production of abnormal hemoglobin S (HbS).¹ It is one of the most prevalent inherited blood disorders in Saudi Arabia. Carrier frequency varies substantially across the country, ranging from approximately 1% in the central provinces to 17% in the eastern and southwestern regions, a distribution that has been attributed in part to longstanding patterns of consanguineous (relative) marriage.^2,3 The considerable national burden of hemoglobinopathies is reflected in data from the Saudi premarital screening program, which reported a prevalence of 49.6 per 1000 individuals between 2011 and 2015.⁴

Vaso-occlusive crisis (VOC) is the hallmark acute complication of SCD and the leading cause of emergency department (ED) visits and unplanned hospitalizations among affected individuals worldwide.⁵ Inadequate or non-standardized pain management contributes to recurrent crises, increased healthcare utilization, prolonged hospital stays, and opioid-related adverse outcomes. Over the past three decades, morphine has become the preferred opioid for the management of VOC in many healthcare systems, largely replacing meperidine following recognition of the neurotoxicity of its metabolite (normeperidine) particularly in patients with renal impairment, as well as its association with seizures and misuse potential.^6,7 Despite these recommendations, meperidine and tramadol are still used as first-line analgesics in several institutions across the Middle East until relatively recently.

King Fahad Armed Forces Hospital (KFAFH) in Jeddah, Saudi Arabia, provides ongoing care for approximately 500 adults with SCD. Prior to pathway implementation, the institution experienced a substantial burden of VOC-related healthcare utilization, with ED visits reaching as many as 1600 presentations per month. Annual opioid consumption totaled 22 488 meperidine vials, 16 275 tramadol vials, and 60 860 tramadol capsules. Frequent repeat presentations for pain management were common, raising concerns regarding the quality and consistency of analgesic care, potential opioid dependence, and inefficient healthcare utilization. Furthermore, no standardized triage or pain-management protocol was in place, and laboratory evaluation was performed inconsistently across presentations.

To address these challenges, a multidisciplinary team of hematologists, clinical pharmacists, and quality improvement specialists developed a structured clinical pathway for the management of SCD-related VOC. The pathway was implemented in May 2017 and subsequently refined through a quality-improvement process to standardize pain assessment, promote evidence-based analgesic prescribing, and improve the consistency of care. Despite the substantial burden of VOC on patients and healthcare systems, published evaluations of structured clinical pathways for SCD pain management in Saudi Arabia remain limited. Therefore, this study aimed to assess the clinical and economic impact of pathway implementation by examining its effects on ED utilization, hospital admissions, readmissions, opioid prescribing patterns, and direct healthcare costs.

METHODS

Study design and setting

This retrospective before-and-after cohort study was conducted at King Fahad Armed Forces Hospital (KFAFH), a 500-bed tertiary referral hospital in Jeddah, Saudi Arabia, operating under the Medical Services Division (MSD) of the Ministry of Defense and Aviation. Outcomes were compared across two consecutive 12-month periods: a pre-pathway period (May 2016–April 2017) and a post-pathway period (May 2017–April 2018). The study protocol was reviewed and approved by the KFAFH Research and Ethics Committee (Reference No. REC 217; approved 13 November 2017). As this was a retrospective study involving review of existing medical records, the Ethics Committee granted a waiver of consent.

Inclusion and exclusion criteria

Patients were eligible for inclusion if they were aged 12 years or older, had a confirmed diagnosis of SCD based on hemoglobin electrophoresis homozygous hemoglobin S (HbSS), hemoglobin SC disease (HbSC), or hemoglobin S/β-thalassemia (HbS/β-thalassemia), had transitioned to adult hematology care, and presented to the ED with an isolated VOC. Formal transfer to adult hematology care was a mandatory eligibility criterion irrespective of chronological age. In practice, the youngest patient captured was 13 years old (Table 1). Patients were excluded if they remained under pediatric hematology follow-up, were pregnant, or presented with other acute SCD-related complications, including fever, hypoxia, acute chest syndrome, priapism, or abdominal pain requiring surgical evaluation.

Table 1.

Baseline demographics and hematological characteristics.

Characteristics	Pre-pathway (n=316)	Post-pathway (n=374)	P value
Age (years)	27.3±8.3	27.2±8.6	.24
Female sex (%)	175 (55.4)	206 (55.1)	>.99
HbSS genotype (%)	214 (67.7)	319 (85.3)	<.001
HbF	7.4±4.9	7.6±5.2	.17
MCV (fL)	82.4±11.0	82.1±10.9	.67
MCH (pg)	28.9±8.5	28.7±8.0	.69
Hydroxyurea use (%)	51 (16.1)	60 (16.0)	.98
Regular clinic followup (%)	83 (26.3)	99 (26.5)	.95
Folic acid compliance (%)	263 (83.2)	311 (83.2)	.99
Thalassemia trait (%)	32 (10.1)	32 (8.6)	.51

SD: standard deviation; HbSS: homozygous hemoglobin S; HbF: fetal hemoglobin; MCV: mean corpuscular volume; MCH: mean corpuscular hemoglobin. Continuous variables are presented as mean SD and were compared using the independent-samples t test. Categorical variables are presented as n (%) and were compared using the chi-square test.

Intervention: The clinical pathway

The clinical pathway was developed in April 2017 following a comprehensive review of the international evidence-based guidelines available at that time. These included the National Heart, Lung, and Blood Institute (NHLBI) evidence-based expert panel report on the management of SCD,⁸ the National Institute for Health and Care Excellence (NICE) guideline on managing acute painful sickle cell episodes in hospital,⁹ and the British Committee for Standards in Haematology (BCSH) guidelines for the management of the acute painful crisis in SCD.¹⁰ Implementation occurred in two phases in accordance with the Plan-Do-Study-Act (PDSA) quality-improvement framework.¹¹ The initial version of the pathway (Appendix 1) was introduced in May 2017. Following an interim evaluation of its performance and feasibility, a revised pathway (Appendix 2) was implemented in July 2017 to further optimize clinical practice. Since the pathway was developed, its core principles have been reinforced by updated international guidance, most notably the 2020 American Society of Hematology (ASH) guidelines for the management of acute and chronic pain in SCD.¹² The NICE guideline was last reviewed in 2023 and was found to require no update; therefore, it remains the current standard.⁹

Initial pathway (Appendix 1)

The initial pathway consisted of a single-track order set designed for the management of isolated acute VOC. The pathway standardized supportive care measures, including hydration, incentive spirometry, and patient comfort interventions, and required routine baseline laboratory investigations comprising a complete blood count with differential, reticulocyte count, urea and electrolytes, liver function tests, and lactate dehydrogenase levels.

Analgesic management was guided by pain severity. Patients with mild pain (score 1–3) received acetaminophen in combination with a nonsteroidal anti-inflammatory drug (NSAID), whereas those with moderate-to-severe pain (score ≥4) were treated with parenteral morphine titrated to achieve adequate pain control. Hydromorphone was reserved for patients with a documented morphine allergy. Meperidine (pethidine) and tramadol were removed from the pathway as first-line analgesic options.

Patients who achieved satisfactory pain control were managed within the ED or day unit, and discharged with appropriate oral analgesia. Patients requiring ongoing IV analgesia, blood transfusion for symptomatic anemia, or IV antibiotic therapy for febrile illness were referred to the on-call medical team for admission to the medical service.

Interim evaluation

All patients with SCA presenting to the ED were prospectively recorded in a dedicated time-stamped registry that was reviewed on a daily basis. In addition, the project team conducted daily rounds on hospitalized patients with SCA to monitor pathway implementation and identify opportunities for improvement. During the first two months following implementation, a reduction in presentations was observed during routine working hours. However, no comparable decrease was seen during after-hours periods (15:30–07:30). Interim review also identified two important practice concerns. First, although meperidine and tramadol were largely eliminated from routine use, morphine was still frequently administered without prior laboratory evaluation and without consistent consideration of pain severity. Second, nearly all SCA presentations were being managed as uncomplicated painful crises and admitted to hospital, despite the heterogeneous and often complex clinical manifestations of SCD. These findings informed subsequent revisions to the clinical pathway.

Revised pathway (Appendix 2)

Based on findings from the interim evaluation, the clinical pathway was revised and implemented in July 2017 (month 3). The principal modification was the introduction of an initial triage step that stratified patients with sickle cell anemia (SCA) according to their presenting complaint, allowing complaint-specific laboratory investigations and specialty consultations when indicated. For patients presenting with an isolated VOC, nonopioid analgesia was initiated while baseline laboratory investigations were obtained to assess disease severity and guide further management. Opioid therapy was escalated only when clinically indicated. Patients whose laboratory findings were unchanged from their established baseline were scheduled for follow-up in the SCA Clinic within one week.

Morphine remained the preferred first-line strong opioid for moderate-to-severe pain (pain score ≥4). Treatment consisted of an initial weight-based IV bolus of 0.05–0.10 mg/kg (maximum 10 mg), with additional doses titrated at 60-min intervals as required. In accordance with current recommendations, the starting dose was individualized based on the dose previously demonstrated to provide effective analgesia during recent presentations.⁹ Hydromorphone was designated for patients with documented morphine allergy, while oxycodone was reserved as a third-line analgesic option.

Patient disposition was determined by response to treatment. Patients achieving adequate pain control and meeting discharge criteria were transitioned to oral analgesia and discharged with outpatient hematology follow-up. Patients with persistent uncontrolled pain after three repeat doses of parenteral opioid therapy were referred to the on-call medical team for admission to the medical service. For admitted patients, analgesia was continued according to the inpatient component of the pathway, including patient-controlled analgesia when appropriate, alongside ongoing supportive care.

Throughout the pathway, acetaminophen and NSAIDs were maintained as adjunctive therapies. Additional supportive medications, including antiemetics, antihistamines, laxatives, and gastroprotective agents, were prescribed as clinically indicated. Venous thromboembolism prophylaxis and naloxone for opioid-induced respiratory depression were also incorporated when appropriate. The revised pathway further introduced explicit admission and discharge criteria, as well as a standardized opioid conversion table to support safe prescribing practices.

Pathway implementation and staff training

The revised clinical pathway was implemented in July 2017 and has remained in continuous clinical use at KFAFH since then. To facilitate implementation, a hospital-wide educational program was conducted for ED and internal medicine physicians and nursing staff. Training sessions focused on pathway objectives, pain assessment, opioid prescribing, patient disposition, and adherence to the standardized management protocol. In parallel, a key performance target was established requiring administration of analgesia within 30 min of patient arrival to the ED. To support this objective and reduce unnecessary hospital admissions, a dedicated Adult Sickle Cell Unit (ASU) was established to manage clinically stable patients presenting with isolated VOC during working hours (07:30–15:30). Ongoing monitoring of pathway adherence was undertaken through daily review of ED presentations and regular multidisciplinary assessment of admitted patients.

Data collection

Data were obtained from multiple institutional sources, including: (1) the KFAFH ED registration system, which was used to identify all visits coded as SCD; (2) the electronic forms system; and (3) the OASIS hospital information system. All patients registered in the ED with SCD recorded as a risk factor were screened for eligibility. Hemoglobin electrophoresis results were reviewed for all patients to confirm the diagnosis of SCD and verify genotype classification. Clinical and demographic data were extracted from the electronic medical record systems. Opioid utilization data were obtained from hospital pharmacy dispensing records, while cost analyses were based on financial data provided by the hospital finance department.

Outcome measures

The primary outcomes were the annual number of ED visits for SCD-related VOC, annual hospital admissions, and the 7-day hospital readmission rate. Secondary outcomes included annual opioid consumption, specifically meperidine (50 mg and 100 mg injections), tramadol (injectable and oral capsule formulations), and morphine. Additional secondary outcomes were annual direct cost savings attributable to changes in opioid utilization and hospital admissions, as well as the median length of hospital stay.

Cost analysis methodology

Direct cost estimates were derived from two sources provided by the KFAFH Finance Department: (1) unit acquisition costs for each opioid formulation, obtained from hospital pharmacy procurement records, and (2) an average direct cost per inpatient admission of 2000 SR, representing bed-day and routine ward nursing costs as costed by the finance department for general medical admissions. Cost savings were calculated by multiplying the observed reduction in opioid use or hospital admissions by the corresponding unit cost. No adjustments were made for inflation, exchange-rate fluctuations, or changes in procurement pricing over time. Therefore, the analysis represents a gross directcost estimate.

Standardization of opioid consumption to morphine milligram equivalents (MME)

Because individual opioid formulations changed in opposing directions, total opioid consumption was additionally standardized to oral MME. This approach was used to determine whether overall systemic opioid exposure decreased despite the increase in morphine use. Total dispensed milligrams for each formulation were calculated by multiplying the number of units dispensed by the labeled unit strength. Injectable formulations were first converted to oral-equivalent doses. A parenteral-to-oral conversion ratio of 1:3 was applied for morphine and meperidine, consistent with standard equianalgesic dosing practices.¹³ A ratio of 1:1 was used for tramadol given its high oral bioavailability. The resulting oral-equivalent doses were multiplied by the standard Centers for Disease Control and Prevention (CDC) oral MME conversion factors for each agent (morphine, ×1; meperidine, ×0.1; tramadol, ×0.1). This yielded final conversion factors of ×3 for injectable morphine, ×0.3 for injectable meperidine, and ×0.1 for both injectable and oral tramadol.¹⁴

Statistical analysis

All analyses were performed using GraphPad Prism version 10 (GraphPad Software, San Diego, CA, USA). Continuous variables are presented as mean ± standard deviation (SD) and were compared between groups using independent-samples t-tests. Length of hospital stay is reported as median. Categorical variables are expressed as frequencies (n) and percentages (%) and were compared using Chi-square test. Differences in hospital admissions, readmissions, and opioid consumption between the pre- and post-pathway periods were assessed using the Chi-square test. Monthly ED visit volumes were summarized descriptively to evaluate trends before and after pathway implementation. Readmission rates are presented with corresponding 95% confidence intervals (95% CIs). A P value <.05 was considered statistically significant. Because this was a retrospective, non-randomized before-and-after comparison without individual patient-level linkage across periods, multivariable adjustments for potential confounders (e.g., genotype distribution, secular practice trends) was not done.

RESULTS

Patient identification and study flow

Patient identification was conducted in two stages (Figure 1). During the pre-pathway period (May 2016–April 2017), 14 615 ED visits were coded as sickle cell anemia (SCA), compared with 4861 visits during the post-pathway period (May 2017–April 2018). After excluding visits by pregnant patients and those still receiving pediatric follow-up, the number of eligible visits decreased to 14 398 and 4508, respectively. A subsequent patient-level review of hemoglobin electrophoresis records led to the exclusion of 92 individuals, including 62 with sickle cell trait, 27 with normal electrophoresis findings, and 3 without on-site electrophoresis results whose laboratory findings were inconsistent with SCD. Following these exclusions, 14 273 visits in the pre-pathway period and 4319 visits in the postpathway period were retained for analysis. These visits corresponded to final cohorts of 316 and 374 unique patients, respectively.

Figure 1.

Patient and Visit Identification Flow Diagram. Flowchart illustrating patient and visit selection for the study cohorts. The diagram shows the total number of emergency department (ED) visits coded as sickle cell anemia (SCA) during the pre- and post-pathway periods, sequential exclusions based on eligibility criteria and diagnostic verification, and the final analytic cohorts included in the analysis.

Demographics and baseline characteristics

Baseline demographic and clinical characteristics of the pre- and post-pathway cohorts are presented in Table 1. Patient ages ranged from 13 to 56 years, and females constituted the majority of participants in both cohorts. A significantly higher proportion of patients in the postpathway cohort had the HbSS genotype than the prepathway cohort 319/374 (85.3%) vs 214/316 (67.7%), P<.001). The higher proportion of HbSS genotype in the post-pathway cohort most plausibly reflects more complete patient-level verification against hemoglobin electrophoresis records, introduced as part of the pathway's structured data-review process (Figure 1), rather than a true shift in the underlying patient population. In both cohorts, 32 patients were identified as having a concomitant thalassemia trait, as indicated by reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) values. Overall engagement in chronic disease management was limited, with only 182 of 690 patients (26.4%) attending regular outpatient follow-up [83/316 (26.3%) prepathway and 99/374 (26.5%) post-pathway] and 116 of 690 (16.8%) demonstrating non-compliance with folic acid supplementation [53/316 (16.8%) and 63/374 (16.8%), respectively. Aside from the difference in HbSS genotype distribution, the two cohorts were comparable with respect to baseline demographics and hematologic characteristics, including age, sex, hydroxyurea use and outpatient clinic follow-up.

ED visits

Implementation of the clinical pathway was associated with a substantial and sustained reduction in SCD-related ED utilization, reflected in both overall visit volume and monthly trends. Total SCD-related ED visits decreased from 14 273 during the pre-pathway year to 4319 during the post-pathway year, representing a 69.7% reduction (P<.001). On a per-patient basis, ED utilization declined from 45.2 to 11.5 visits per patient-year.

Analysis of monthly visit patterns revealed two notable findings (Figure 2). First, ED utilization increased steadily throughout the pre-pathway period, rising from approximately 950 visits in May 2016 to 1500–1600 visits by March 2017, indicating a progressively worsening burden of SCD-related ED use prior to intervention. Second, during the initial two months following pathway implementation (May–June 2017), monthly visit volumes remained comparable to pre-pathway levels, consistent with a transitional phase involving staff training and patient adaptation. Following the pathway revision introduced in month 3 (July 2017), ED visits declined sharply to approximately 440 per month, representing a 51% reduction compared with the corresponding month in the pre-pathway period. Thereafter, monthly visit volumes remained consistently low, ranging from 180 to 290 visits per month. By the final month of follow-up, ED utilization had fallen by 88% relative to pre-pathway levels. These reductions were maintained throughout the latter half of the postimplementation period, suggesting a durable and sustained effect of the intervention rather than a transient change in healthcare utilization patterns.

Figure 2.

Monthly emergency department visits for sickle cell disease–related vaso-occlusive crises before and after clinical pathway implementation. ED utilization increased progressively during the pre-pathway period, reaching a peak of 1,587 visits in March 2017. Following pathway implementation, visit volumes remained comparable to pre-pathway levels during the initial transition period (May–June 2017) before declining sharply after the pathway revision introduced in July 2017 (month 3). Reduced visit volumes were sustained throughout the remainder of the follow-up period.

Hospital admissions and readmissions

Implementation of the clinical pathway was associated with significant reductions in both hospital admissions and early readmissions for patients with SCD (Figure 3). Annual hospital admissions decreased from 520 to 349, representing a 32.9% reduction (171 fewer admissions; P<.001). Similarly, 7-day readmissions declined from 151 to 46, corresponding to a 69.5% reduction (105 fewer readmissions; P<.001). The 7-day readmission rate decreased from 29.1% (95% CI, 25.0–33.6%) before implementation to 13.2% (95% CI, 9.8–17.4%) afterwards. This represented an absolute reduction of 15.9% points and a relative reduction of 54.6%. In addition, the median length of hospital stay was substantially reduced, falling from 11 days in the pre-implementation period to 4.3 days following pathway implementation.

Figure 3.

Annual hospital admissions and 7-day readmissions for sickle cell disease before and after clinical pathway implementation. Comparison of annual hospital admissions and 7-day readmissions among patients with sickle cell disease (SCD) during the pre- and post-pathway periods. Both outcomes decreased significantly following pathway implementation, with reductions in hospital admissions and early readmissions reaching statistical significance (P<.001 for both comparisons).

Opioid consumption

The clinical pathway successfully shifted opioid prescribing away from meperidine and tramadol toward morphine. Consumption of meperidine and tramadol decreased significantly across all formulations, with reductions ranging from 33.4% to 54.1% (all P<.001). The greatest reduction was observed for tramadol capsules (54.1%). Detailed consumption data for each formulation are presented in Table 2. In contrast, morphine utilization increased by 41.2%, reflecting the pathway's intended strategy of establishing morphine as the preferred first-line opioid for moderate-to-severe pain. Despite this change, a notable proportion of patients declined IV morphine and specifically requested intramuscular meperidine, highlighting the need for targeted patient education and behavioral interventions to support adherence to evidence-based analgesic practices. Hydromorphone and oxycodone were introduced only after implementation of the clinical pathway and were therefore unavailable during the preintervention period, precluding comparative analyses for these agents.

Table 2.

Annual opioid consumption before and after clinical pathway implementation.

Medication	Pre-pathway units	Post-pathway units	Reduction (%)	P value
Meperidine injection 100 mg	12 053	8032	4021 (33.4)	<.001
Meperidine injection 50 mg	10 435	6094	4341 (41.6)	<.001
Tramadol injection 100 mg	16 275	10 821	5454 (33.5)	<.001
Tramadol capsule 50 mg	60 860	27 930	32 930 (54.1)	<.001
Morphine injection 10 mg/mL	10 090	14 245	+4155 (+41.2)	<.001

When opioid use was standardized to oral MME to account for differences across formulations, total annual opioid consumption decreased from approximately 1 287 865 MME before pathway implementation to 1 007 580 MME after implementation. This represents a 21.8% reduction (Table 3). Because the post-pathway cohort included more unique patients, opioid exposure per patient-year provides a more meaningful comparison. This measure decreased from approximately 4075 MME/patient/year to 2694 MME/patient/year, representing a 33.9% reduction. These findings indicate that the increase in morphine use was accompanied by an overall reduction in systemic opioid exposure. The results therefore support improved opioid stewardship rather than simple substitution of one opioid for another.

Table 3.

Total opioid consumption standardized to oral morphine milligram equivalents (MME) pre- and post-pathway implementation.

Medication	Total mg dispensed (Pre-pathway)	Total mg dispensed (Post-pathway)	MME conversion factor	Total MME (Pre-pathway)	Total MME (Post-pathway)
Meperidine injection 100 mg	1 205 300	803 200	×0.3	361 590	240 960
Meperidine injection 50 mg	521 750	304 700	×0.3	156 525	91 410
Tramadol injection 100 mg	1 627 500	1 082 100	×0.1	162 750	108 210
Tramadol capsule 50 mg	3 043 000	1 396 500	×0.1	304 300	139 650
Morphine injection 10 mg/mL	100 900	142 450	×3	302 700	427 350
Total	6 498 450	3 728 950	—	1 287 865	1 007 580

Cost analysis

Implementation of the clinical pathway resulted in annual direct cost savings of 410 709 Saudi Riyals (SR) (approximately 109 522 USD). The majority of these savings were attributable to reductions in hospital admissions, accounting for 342 000 SR, while decreased opioid consumption contributed an additional 68 709 SR. Cost savings from reduced admissions were estimated based on 171 averted admissions and a conservative direct cost of 2000 SR per admission, excluding overhead expenses. The detailed cost breakdown by opioid formulation is presented in Table 4. Importantly, these estimates reflect only direct costs and do not include indirect costs, intensive care unit transfers, diagnostic investigations, consultant fees, or institutional overhead. Consequently, the overall economic impact of the clinical pathway is likely to be substantially greater than reported.

Table 4.

Annual direct cost savings before and after clinical pathway implementation.

Cost category	Pre-pathway (SR)	Post-pathway (SR)	Annual Saving (SR)	Savings (%)
Meperidine 100 mg injections	27 722	18 474	9248	33.4
Meperidine 50 mg injections	24 000	14 016	9984	41.6
Tramadol capsules 50 mg	51 122	23 461	27 661	54.1
Tramadol injections 100 mg	65 100	43 284	21 816	33.5
Narcotics subtotal	167 944	99 235	68 709	40.9
Admission cost (2000 SR/admission)	1 040 000	698 000	342 000	32.9
Total combined savings	1 207 944	797 235	410 709	34.0

SR: Saudi Riyal. Admission cost calculated at 2000 SR per hospital admission, excluding overhead

DISCUSSION

This study evaluated the implementation of a multidisciplinary clinical pathway for the management of VOC among adults with SCD in a large tertiary-care hospital in Saudi Arabia. Pathway implementation was associated with substantial reductions in ED utilization, hospital admissions, early readmissions, and healthcare costs, while simultaneously promoting evidence-based opioid prescribing practices. These findings suggest that standardized, pathway-driven management can improve the efficiency and consistency of care for patients with SCD and reduce the burden of VOC on healthcare systems.

The most notable finding was the marked reduction in ED utilization following pathway implementation. Annual VOC-related ED visits decreased by nearly 70%, with sustained reductions observed throughout the post-implementation period. Importantly, monthly visit volumes remained relatively unchanged during the first two months after implementation before declining sharply following pathway revision and refinement. This pattern supports the importance of continuous qualityimprovement processes and iterative pathway optimization rather than reliance on a single intervention, consistent with the Plan-Do-Study-Act (PDSA) framework recommended for clinical quality improvement initiatives.¹¹ The observed reduction likely reflects several complementary mechanisms, including improved pain management, more standardized triage, enhanced outpatient follow-up, and the availability of alternative care pathways through the ASU. Previous studies evaluating structured SCD management programs have similarly reported reductions in acute healthcare utilization, although the magnitude of improvement varies across institutions depending on patient populations, baseline practices, and available healthcare resources.^15–17 However, the magnitude of this reduction should be interpreted with some caution, as several factors beyond the clinical pathway itself may have contributed, including possible diversion of clinically stable patients to the newly established ASU, enhanced outpatient follow-up reducing repeat crises, and secular trends in SCD care unrelated to the pathway.

The reduction in hospital admissions and early readmissions further suggests improvements in both acute management and discharge decision-making. Hospital admissions decreased by approximately onethird, while 7-day readmissions were reduced by more than half. These findings indicate that patients achieved more effective symptom control during the initial encounter and were less likely to require early return to care. The introduction of standardized admission and discharge criteria likely improved consistency in clinical decision-making and reduced practice variation among providers. In addition, the ASU allowed clinically stable patients to receive ongoing observation and analgesic treatment without inpatient admission, thereby reducing hospital bed utilization while maintaining continuity of care. Similar benefits have been reported in dedicated observation-based SCD programs, which have demonstrated lower admission rates compared with conventional ED management.¹⁵

A key component of the pathway was the transition from meperidine and tramadol toward morphine-based analgesia. Contemporary international guidelines recommend morphine as a preferred opioid for moderate-to-severe VOC pain because of its established efficacy, predictable pharmacokinetic profile, and more favorable safety characteristics compared with meperidine.^9,12 Meperidine is associated with accumulation of the neurotoxic metabolite normeperidine, particularly in patients with impaired renal function, and has been linked to central nervous system toxicity including seizures.¹⁸ Consistent with these recommendations, implementation of the pathway resulted in substantial reductions in meperidine and tramadol utilization accompanied by increased morphine use. This shift reflects improved alignment with evidence-based practice and demonstrates the potential value of clinical pathways as opioid stewardship tools. Tramadol misuse, in particular, has been identified as a growing public health concern in the Middle East region, lending additional importance to pathway-driven reductions in tramadol consumption.¹⁹ Nevertheless, continued prescribing of meperidine and tramadol outside pathway-directed services highlights the need for broader institutional engagement and ongoing educational initiatives to support sustained practice change.

The observed reduction in median hospital length of stay is also clinically relevant. Median length of stay decreased from 11 days to 4.3 days following pathway implementation, approaching the 4–6 day range reported in international pathway-managed SCD cohorts.^16,17 Shorter hospitalization may reflect earlier initiation of effective analgesia, more standardized treatment escalation, clearer discharge criteria, and improved coordination between emergency, hematology, and inpatient teams. Reduced length of stay not only benefits patients by minimizing disruption to daily activities but also improves hospital capacity and resource utilization.

From an economic perspective, implementation of the pathway generated substantial direct cost savings. Most savings were attributable to reductions in hospital admissions, with additional savings resulting from changes in opioid utilization. Because the analysis excluded indirect costs, overhead expenses, intensive care utilization, diagnostic testing, consultant services, and productivity losses, the true economic benefit is likely underestimated. These findings are consistent with previous reports demonstrating that structured care pathways can improve both clinical outcomes and healthcare efficiency by reducing avoidable utilization of high-cost services.^16,17

The findings are particularly relevant in the Saudi Arabian settingst, where SCD remains highly prevalent and places a considerable burden on emergency and inpatient services. Despite this burden, published evaluations of structured VOC management pathways within the region remain limited.²⁰ The present study, therefore, contributes important regional evidence supporting the adoption of standardized multidisciplinary approaches to VOC management. A recent multicenter Saudi study confirmed that morphine and paracetamol are now the predominant analgesics for acute VOC nationally, yet documented persistent inter-hospital variation in opioid prescribing that underscores the continued need for institutionally embedded standardized protocols.²¹ A concurrent survey of emergency physicians in the western region of Saudi Arabia further found that significant variation in opioid prescribing and discharge practices persisted across institutions, reinforcing the gap between policy intent and clinical implementation.²² Furthermore, the intervention incorporated several elements emphasized in contemporary SCD care models, including rapid analgesia delivery, standardized pain assessment, opioid stewardship, laboratory-guided clinical evaluation, and coordinated outpatient follow-up.¹² These principles remain applicable despite ongoing advances in disease-modifying therapies and continue to represent key components of high-quality acute SCD care. The present study was conducted and reported in accordance with the SQUIRE 2.0 framework for quality improvement reporting, ensuring methodological transparency and reproducibility.²³

Several limitations should be considered when interpreting these findings. First, this was a single-center study conducted at a tertiary-care hospital, which may limit the generalizability of the results to other healthcare settings. However, the study population is broadly representative of urban adult patients with sickle cell disease in western Saudi Arabia.^20,21 Second, the uncontrolled retrospective before-and-after design limits the ability to exclude the influence of factors unrelated to the pathway. Concurrent changes in institutional infrastructure, staffing levels, physician prescribing practices, or other quality improvement initiatives may have occurred during the study period. Any of these factors could have contributed to the observed reductions in ED utilization, length of stay, and readmissions. A segmented regression analysis could have distinguished the effects of the pathway from broader temporal changes. However, this analysis was not feasible with the available visit-level data. Future prospective or multicenter studies should incorporate such methods to provide a more rigorous evaluation of pathway effectiveness. Third, the proportion of patients with the HbSS genotype was significantly higher in the postpathway cohort than in the pre-pathway cohort (85.3% vs. 67.7%). Because genotype-specific outcomes could not be linked to individual encounters in this retrospective dataset, adjustment for this imbalance was not feasible.

Fourth, adherence to the pathway was not complete. Meperidine and tramadol continued to be prescribed in some clinical areas outside the direct oversight of the pathway team. Similar challenges have been reported in other implementation studies and represent a common barrier to achieving full protocol adherence.²² Fifth, patient-reported outcomes, including pain relief, satisfaction with care, and health-related quality of life, were not routinely collected and therefore could not be assessed. Sixth, the cost analysis was limited to a simplified estimate of gross direct costs, based on bed-day pricing and drug acquisition costs, and did not include the operational costs of establishing and maintaining the pathway (e.g., additional nursing time, ASU staffing, ED rapid-track resources, or administrative oversight). These unmeasured costs may partially offset the estimated savings. Therefore, the reported economic benefit should be considered an approximation rather than a comprehensive cost-effectiveness evaluation.

These limitations are balanced by several strengths. The study covered two consecutive 12-month periods, with SCD diagnosis and genotype verified by hemoglobin electrophoresis rather than administrative coding alone. Outcomes were obtained from multiple institutional data sources, enhancing the reliability of the findings. Standardization of opioid use to oral MME allowed overall opioid exposure to be assessed despite differing trends across individual agents. Finally, evaluation of the pathway under routine clinical conditions enhances the real-world relevance and potential applicability of the findings to similar healthcare settings.

CONCLUSIONS

Implementation of a multidisciplinary clinical pathway for adults presenting with SCD-related VOC was associated with substantial reductions in ED utilization, hospital admissions, early readmissions, hospital length of stay, and direct healthcare costs. The pathway also facilitated a transition toward evidence-based opioid prescribing through increased use of morphine and reduced reliance on meperidine and tramadol, in line with current ASH and NICE recommendations.^9,12 These findings support the role of standardized clinical pathways as an effective strategy for improving the quality, consistency, and efficiency of acute SCD care. Future multicenter studies are warranted to confirm these findings and evaluate long-term patient-centered outcomes across diverse healthcare settings.

SUPPLEMENTS

Appendix 1.

Appendix 2.

Funding Statement

None.