The Quality Improvement Review Board: An Innovative Approach to Oversight of Projects That Do Not Meet Criteria of Human Subject Research.

This article describes the development of an institutional quality improvement review board (QIRB) as an effective and efficient method for reviewing and overseeing institutional quality improvement (QI) initiatives. QI projects involve the systematic collection and analysis of data and the implementation of interventions designed to improve the quality of clinical care and/or educational programs for a distinct population in a specific setting. QI projects are fundamentally distinct from human subjects research (HuSR); however, the differences between them are subtle and highly nuanced. Determining whether a project meets the definition of QI or qualifies as HuSR, thus requiring institutional review board (IRB) review, can be confusing and frustrating. Nevertheless, this distinction is highly consequential due to the heavy regulatory requirements involved in HuSR and IRB oversight. Making the correct determination of a project's regulatory status is essential before the project begins. Project leaders may not realize that their work meets the definition of HuSR and, therefore, might conduct the project without appropriate IRB review. Therefore, best practices dictate that project leaders should not decide which type of institutional review is appropriate for their projects. In addition, when QI project teams attempt to disseminate the results of their work, documentation of formal review and approval is generally required by peer-reviewed journals and professional organizations. However, institutional review mechanisms are rarely available. Projects that do not meet the definition of HuSR fall outside the purview of IRBs and most institutions do not have an alternative review body. This creates frustration for both project leaders and IRB administrators. Apart from IRB review, a separate process for reviewing QI projects offers several benefits. These include (1) relieving the burden on busy IRB staff; (2) promoting scholarly activity; (3) protecting the institution, project leaders, and participants from HuSR conducted outside of appropriate IRB review; and (4) promoting rigorous QI methods.

Using the HyFlex model to deliver a capstone seminar course.

INTRODUCTION: The HyFlex course structure allows students to attend class in-person or via synchronous videoconferencing technology. This model has been described, but no data are available in pharmacy curricula. METHODS: Students enrolled in Grand Rounds (GR) were eligible. The GR Engagement Assessment Tool (GREAT) measured engagement three times during the semester. Eighteen statements across four domains were rated using a five-point Likert scale (1 = not true at all and 5 = completely true). Free-text responses were collected for qualitative analysis. The primary outcome was the difference in GR engagement between students attending in-person vs. remotely. Descriptive statistics were used for demographic information. Wilcoxon rank-sum tests compared Likert-scale responses between in-person and remote attendance. RESULTS: Surveys included 128 responses from 88 unique students. There were no differences between remote and in-person attendance for the boredom and elaboration domains. In-person students reported listening more intently (median 4, IQR [3,4]; P = .03). In-person students felt the material was more practical (median 4, IQR [4,5]) than remote students (median 4, IQR [3,4]; P = .002) and more applicable to other situations (median 3, IQR [3,5]) than remote students (median 3, IQR [2,4]; P = .04). Qualitative analysis of the entire cohort demonstrated five themes for satisfaction: safety, flexibility, convenience, technology, and professionalism. CONCLUSIONS: There were subtle differences in student engagement or satisfaction using the HyFlex model. This study supports the expansion of this methodology to similar courses where remote instruction is needed.

Efficacy and benefits of mock residency interviews.

INTRODUCTION: Obtaining a residency has become more competitive as more pharmacy students seek postgraduate training. This is likely due to pharmacist positions increasing in clinical settings. To be fully prepared, students seeking residency positions should be trained for the interview process by their pharmacy school. METHODS: Mock residency interviews (MRI) were conducted at the Texas Tech University Health Sciences Center School of Pharmacy which included components of typical residency interviews. The primary outcome compared residency match rates for MRI participants vs. non-participants. Secondary outcomes evaluated student preparedness, student and faculty feedback, and satisfaction/benefit of the event along with comparison of school vs. national match rate and assessment of those matching compared to grade point average (GPA). RESULTS: Match rates were similar between MRI participants vs. non-participants (75% vs. 73%) with significant difference in Phase I match rates between MRI participants vs. non-participants (75% vs. 51%, P = .007). MRI was significantly associated with Phase I matching in the multivariable analysis (odds ratio (OR) = 2.81, 95% CI 1.27-6.22). The overall school's match rate exceeded the national two out of three years in the quality improvement project period. GPA was the only other factor independently associated with Phase I matching (OR = 1.15, 95% CI 1.01-1.32). Students and faculty consistently reported positive feedback following participation. CONCLUSIONS: MRI are valuable and are making a difference as indicated by improved Phase I match rates for those that participated. Students and faculty reported an increase in preparedness and overall satisfaction after attending MRI.

Do the types and routes of proton pump inhibitor treatments affect clostridium difficile in ICU patients? A retrospective cohort study.

Background: : Proton pump inhibitors (PPI) are associated with Clostridium difficile infection (CDI). Impact of the route of administration is unknown.Research Design and Methods: Patients in Multiparameter Intelligent Monitoring in Intensive Care II database (MIMIC-II) from 2001 to 2008, >18 years old, admitted to medical, surgical, or cardiac ICUs were included. PPI exposures were omeprazole, esomeprazole, lansoprazole, and pantoprazole. PPI administration routes were oral or intravenous. Patients who received histamine receptor antagonists (H2RA) were the control arm. CDI was identified using ICD-9 diagnostic code 008.45. Multiple logistic regression analysis was performed to calculate odds ratios (OR).Results: The study included 16,820 patients (57% male) with a mean age of 63 (SD±17) years and hospitalization duration of 10.2 days (SD±11). Pantoprazole was the most common PPI (94%). CDI occurred in 2.4% and more in patients receiving PPIs than H2RAs (3.0% vs. 0.8%, p < 0.001). CDI prevalence increased with intravenous (95%CI = 1.69-3.39, OR 2.4) and oral (95%CI = 1.59-3.27, OR 2.3) PPI use compared to H2RAs. CDI prevalence was not associated with PPI route in the multivariable model (OR 1.07, 95%CI 0.86-1.34).Conclusions: Both intravenous and oral PPI use in the ICU were independently associated with CDI.

An evaluation of tedizolid for the treatment of MRSA infections.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA)is a common pathogen in acute bacterial skin and soft tissue infections (ABSSSIs), nosocomial pneumonia, bacteremia, endocarditis, as well as diabetic foot, bone, and joint infections. Areas covered: This review summarizes the randomized controlled trials that evaluated the clinical efficacy of tedizolid in ABSSSIs, which is currently the only United States Food and Drug Administration-labeled indication for tedizolid. Expert opinion: Tedizolid has several potential advantages over linezolid including once-daily dosing, shorter duration of therapy, and increased tolerability. However, its cost will likely limit its adoption for ABSSSIs with MRSA because other oxazolidinone antibiotics are available in less costly generic versions. Tedizolid is also currently being investigated for its use in other MRSA infections including nosocomial pneumonia as well as diabetic foot, bone, and joint infections and tedizolid's use in these disease states appears more promising. Potential indications for future clinical investigation of tedizolid's efficacy and safety include bacteremia and meningitis.

Challenges with Diagnosing and Managing Sepsis in Older Adults.

Sepsis in older adults has many challenges that affect rate of septic diagnosis, treatment, and monitoring parameters. Numerous age-related changes and comorbidities contribute to increased risk of infections in older adults, but also atypical symptomatology that delays diagnosis. Due to various pharmacokinetic/pharmacodynamic changes in the older adult, medications are absorbed, metabolized, and eliminated at different rates as compared to younger adults, which increases risk of adverse drug reactions due to use of drug therapy needed for sepsis management. This review provides information to aid in diagnosis and offers recommendations for monitoring and treating sepsis in the older adult population.

Assessment of the intensive care unit treatment of pneumonia at a veterans affairs facility.

INTRODUCTION: Pneumonia is a common cause of morbidity and mortality in the critically ill. Clinicians use a range of duration for antibiotic treatment from 7 to 14 days or longer. Failure to de-escalate antimicrobial therapy in a timely manner may lead to increased antimicrobial resistance, increased risk of side effects, and increased cost. OBJECTIVE: To investigate potential methods to improve treatment of pneumonia for patients in 4 intensive care units (ICUs). METHODS: A retrospective descriptive chart review was conducted at the Veterans Affairs North Texas Health Care System (VANTHCS). Veterans aged 18 to 90 years admitted to the ICU with a diagnosis of pneumonia were included. Descriptive statistics were used to interpret the data. Current management was reviewed to identify markers such as length of antibiotic therapy, ICU length of stay, and inpatient mortality. Secondary objectives included appropriateness and accuracy of the empiric regimen. RESULTS: Of the 1,854 Veterans admitted, 107 met inclusion criteria. Antibiotic choices for positive cultures were appropriate in 45 out of 46 (98%) patients, with an average length of therapy of 8.6 ± 6.3 days. De-escalation of antibiotics based on sensitivity data occurred in 73% of positive cultures. CONCLUSIONS: Pneumonia in the VANTHCS ICUs is initially treated with empiric antibiotics. Empiric antibiotic therapy for pneumonia was appropriate and accurate over this time period. Opportunities exist for de-escalation in patients with or without positive cultures. The procalcitonin assay is now being utilized at VANTHCS to optimize patient care.

Enteral naloxone for the treatment of opioid-induced constipation in the medical intensive care unit.

PURPOSE: To determine the safety and efficacy of enteral naloxone for the treatment of opioid-induced constipation in the medical intensive care unit (MICU). MATERIALS AND METHODS: This descriptive study included patients aged 18 to 89 years admitted to the MICU between July 1, 2007, and June 30, 2012, who received scheduled opioids and at least 1 dose of enteral naloxone. All data were obtained from electronic charting systems. Efficacy was assessed by evaluating time to bowel movement (BM), number of naloxone doses until BM, and ability to tolerate tube feeds after receipt of enteral naloxone. Safety was assessed by comparing opioid requirements, heart rates, and systolic blood pressures before and during naloxone treatment. RESULTS: Fifteen of the 16 patients included in the final analysis passed BMs during the study period. The median time to BM was 24.4 hours. The median number of naloxone doses received prior to passing a BM was 3. Seventy-eight percent of patients who were not receiving tube feeds at the time of naloxone administration received continuous tube feeds after naloxone initiation. No adverse effects associated with use of enteral naloxone were noted. CONCLUSIONS: Enteral naloxone appears safe for the treatment of opioid-induced constipation in the MICU. Enteral naloxone may be effective in treating opioid-induced constipation; however, further studies are warranted.

Para-dichlorobenzene toxicity - a review of potential neurotoxic manifestations.

BACKGROUND: Para-dichlorobenzene (PDCB) is an active ingredient of mothballs, deodorizers and fumigants. Due to the easy availability of this chemical, there is a considerable risk for accidental or intentional toxic exposure. Recently, multiple cases of PDCB toxicity due to mothball ingestion were reported. PDCB toxicity can affect multiple organ systems including liver, kidneys, skin, lung and the central nervous system (CNS). CNS toxicity often results in leukoencephalopathy and heterogeneous neurological manifestations. OBJECTIVES: The objective of this study was to illustrate the clinical presentation, imaging findings, diagnosis and management of PDCB toxicity. METHODS: We carried out a literature review of the pharmacological and toxicological properties of PDCB. CONCLUSIONS: PDCB and other aromatic hydrocarbons are capable of CNS tissue damage and in promoting functional neurological decline. While very little is currently known about prevalence of PDCB addiction, it cannot be ruled out that its illicit use among young people is under-recognized. The number of cases of PDCB toxicity might also rise due to the increasing industrial and domestic use of this chemical.

Risk factors for and impact of methicillin-resistant Staphylococcus aureus nasal colonization in patients in a medical intensive care unit.

This retrospective cohort study investigated the impact and predictive factors of methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization in 180 patients admitted to a medical intensive care unit between July 2009 and June 2010. No significant associations between MRSA nasal colonization and the incidence of health care-associated multidrug-resistant-related infections, intensive care unit length of stay, or inpatient mortality were found. Significant risk factors for MRSA colonization included previous medical history of diabetes mellitus and congestive heart failure.

Can Pharmacokinetic and Pharmacodynamic Principles Be Applied to the Treatment of Multidrug-Resistant Acinetobacter?

OBJECTIVE: To discuss treatment options that can be used for treatment of Acinetobac/erinfections. DATA SOURCES: A MEDLINE search (1966-November 2010) was conducted to identify English-language literature on pharmacotherapy of Acinetobacter and the bibliographies of pertinent articles. Programs and abstracts from infectious diseases meetings were also searched. Search terms included Acinetobacter, multidrug resistance, pharmacokinetics, pharmacodynamics, Monte Carlo simulation, nosocomial pneumonia, carbapenems, polymyxins, sulbactam, aminoglycosides, tetracyclines, tigecycline, rifampin, and fluoroquinolones. DATA SELECTION AND DATA EXTRACTION: All articles were critically evaluated and all pertinent information was included in this review. DATA SYNTHESIS: Multidrug resistant (MDR) Acinetobacter, defined as resistance to 3 or more antimicrobial classes, has increased over the past decade. The incidence of carbapenem-resistant Acinetobacter is also increasing, leading to an increased use of dose optimization techniques and/or alternative antimicrobials, which is driven by local susceptibility patterns. However, Acinetobacter infections that are resistant to all commercially available antibiotics have been reported. General principles are available to guide dose optimization of aminoglycosides, ß-lactams, fluoroquinolones, and tigecycline for infections due to gram-negative pathogens. Unfortunately, data specific to patients with Acinetobacter infections are limited. Recent pharmacokinetic-pharmacodynamic information has shed light on colistin dosing. The dilemma with colistin is its concentration-dependent killing, which makes once-daily dosing seem like an attractive option, but its short postantibiotic effect limits a clinician's ability to extend the dosing interval. Localized delivery of antimicrobials is also an attractive option due to the ability to increase drug concentration at the infection site while minimizing systemic adverse events, but more data are needed regarding this approach. CONCLUSIONS: Increased reliance on dosage optimization, combination therapy, and localized delivery of antimicrobials are methods to pursue positive clinical outcomes in MDR Acinetobacter infections since novel antimicrobials will not be available for several years. Well-designed clinical trials with MDR Acinetobacter are needed to define the best treatment options for these patients.

Evaluation of empiric antibiotic use in surgical sepsis.

BACKGROUND: We performed an evaluation of antimicrobial guidelines for patients with surgical sepsis. METHODS: The purpose of this study was to validate current empiric antibiotic recommendations in our sepsis protocol based on the suspected site of infection. The primary objective was to assess the appropriateness of empiric antibiotic recommendations and to determine if initial empiric antibiotics provided adequate coverage compared with sensitivity data (accuracy). Secondary end points included antibiotic protocol compliance, intensive care unit (ICU)-free days, and mortality. RESULTS: Appropriate antibiotics were prescribed in 82% of patients. Of the culture-positive patients, 72% received accurate antibiotics. ICU-free days were greater for patients in the compliant group (14.5 vs 8.4; P = .014). Hospital mortality was greater in patients who were noncompliant with protocol recommendations (22% vs 17%; P = .44). CONCLUSIONS: Our current antibiotic guidelines provide appropriate and accurate antimicrobial coverage. Noncompliance with the antibiotic protocol resulted in fewer ICU-free days and increased hospital mortality in surgical sepsis patients.

Intravenous to oral conversion of antihypertensives: a toolkit for guideline development.

OBJECTIVE: To provide a toolkit of information for hospitals to use in developing intravenous to oral conversion protocols for antihypertensives. DATA SOURCES: Articles describing intravenous to oral conversion protocols for any therapeutic category were identified in an English-language MEDLINE search (1990-April 2010) using a wide variety of MeSH terms. References from selected articles were reviewed for additional material. STUDY SELECTION AND DATA EXTRACTION: Experimental and observational English-language studies and review articles that focused on oral transition of intravenous drugs were selected. DATA SYNTHESIS: Most of the literature on conversion from intravenous to oral formulations involves antimicrobials. There is considerable evidence documenting reduced costs and improved patient flow through the health-care system following implementing these protocols with drugs like antimicrobials, histamine-2 receptor antagonists, and proton pump inhibitors. Although antihypertensives have not been studied, principles and implementation strategies used for other drug classes can be applied to antihypertensives. Guidance is provided on framing the problem, issues surrounding oral absorption principles, information pertaining to oral conversion in specific disease states, and implementation and documentation strategies. Detailed tables of oral and intravenous antihypertensives are provided. CONCLUSIONS: We recommend that hospitals consider developing protocols on conversion of intravenous to oral antihypertensives in an attempt to reduce unnecessarily prolonged intravenous therapy. Information contained in this article can be used as a toolkit to select information specific to the characteristics of individual health-care systems.

Symposium on roles of and cooperation between academic- and practice-based pharmacy clinicians.

PURPOSE: The findings of an academic symposium as they relate to the history and role of the academic pharmacy clinician, the strengths and limitations of the academic pharmacy clinician model, and the framework for future synergistic work relations among clinical pharmacy practitioners are summarized. SUMMARY: On April 23, 2008, a symposium was convened to bring key thought leaders together to discuss the relationship of the academic-based pharmacy clinician and the practice-based pharmacy clinician. Participants included clinical faculty and administrators from two colleges of pharmacy, practice-based clinical pharmacists and pharmacy managers from seven health care institutions, and representatives from the American Association of Colleges of Pharmacy, the American College of Clinical Pharmacy, and the American Society of Health-System Pharmacists. Symposium participants discussed the roles and expectations of clinical pharmacists based on primary affiliation within the contemporary practice model for academic- and practice-based pharmacy clinicians and identified sources of conflict for academic- and practice-based pharmacy clinicians. Symposium participants agreed that in order to succeed, the academic-based and the practice-based pharmacy clinicians must function in a true partnership as each individual has strengths, resources, and benefits to bring to the relationship. Furthermore, knowledge, consideration, and an understanding of the potentially different goals and objectives of each institution are critical. CONCLUSION: A symposium attended by clinical faculty members and administrators from two colleges of pharmacy, practice-based clinical pharmacists and pharmacy managers from seven health care institutions, and representatives from three national pharmacy organizations was conducted to discuss the roles of and cooperation between academic- and practice-based pharmacy clinicians.

Recombinant factor VIIa treatment of severe bleeding in cardiac surgery patients: a retrospective analysis of dosing, efficacy, and safety outcomes.

OBJECTIVE: To describe rFVIIa dosing and clinical outcomes in cardiovascular surgery patients with refractory bleeding. DESIGN: Retrospective chart review of patients receiving rFVIIa from January 1, 2004 to September 30, 2005, in the cardiovascular surgery setting. SETTING: Tertiary care, private teaching hospital. PARTICIPANTS: Ninety-three patients who received rFVIIa after cardiovascular surgery for the management of refractory bleeding. INTERVENTIONS: None. MEASURES AND MAIN RESULTS: Patients received an average of 7.6 +/- 6.8 units of red blood cells (RBCs) before rFVIIa dosing (mean dose, 56.2 +/- 26.5 microg/kg). Median and 25th and 75th quartile blood product consumption was significantly reduced 6 hours after rFVIIa versus 6 hours before (RBCs, -3 units, [-1, -7]; cryoprecipitate, -7.5 units [0, -20]; platelet, -3 units [-1, -4]; fresh frozen plasma, -4 units [-2, -7]). Repeated rFVIIa dosing occurred in 10% of patients, with 8 (8.6%) and 2 (2.25%) patients receiving second and third doses, respectively. Subgroup analysis of each rFVIIa dosing quartile >30 microg/kg showed a significant reduction in RBCs; however, no significant differences were found in the magnitude of RBC reduction or percent of patients requiring massive transfusion among the quartiles. No adverse thrombotic episodes were noted, and the observed mortality (22.6%) was not attributed to rFVIIa therapy. CONCLUSIONS: rFVIIa effectively reduces blood product use in cardiovascular surgery patients having massive blood loss. Although the optimal dose of rFVIIa for use in cardiovascular surgery remains undetermined, these data provide evidence that dosing regimens using <90 microg/kg are effective in this population and may provide guidance for centers establishing standardized protocols for rFVIIa use in cardiovascular surgery patients.

Significant publications on infectious diseases pharmacotherapy in 2007.

PURPOSE: Significant publications on infectious diseases (ID) pharmacotherapy in 2007 were compiled and summarized. SUMMARY: On January 2, 2008, the 21 members of the Houston Infectious Disease Network (HIDN) were asked to select an article that was published in a peer-reviewed journal between January 1 and December 31, 2007, and write a summary highlighting why the article was significant to the diagnosis or treatment of ID. Articles were selected based on prior "top 10" presentations at major ID and pharmacy meetings or were listed as major articles in prominent ID journals. Priority was given to peer-reviewed publications and nationally recognized clinical treatment guidelines. Nineteen articles and summaries were submitted by HIDN members. The publication listing was distributed to Society of Infectious Diseases Pharmacists members via an Internet survey in early February 2008. Members were asked to select the 10 most significant articles relating to ID pharmacotherapy from the list of 19 and were allowed to add an additional article that was not already listed. A total of 102 individuals participated in the survey. A listing of the top 10 articles published in 2007 and one honorable mention was compiled, and the significance of each article was summarized. CONCLUSION: The increased number of articles in the peer-reviewed medical literature related to the diagnosis and treatment of ID has made it challenging to maintain a contemporary knowledge base of key publications. This summary of significant ID articles published in 2007 can help to alleviate the burden of knowledge management.

Discontinuation and reinstitution of medications during the perioperative period.

PURPOSE: The issues regarding the discontinuation and reinstitution of long-term therapies, including cardiovascular agents, anticoagulants and antiplatelet agents, central nervous system agents, and herbal medicines, in the perioperative period are discussed. SUMMARY: It is estimated that one fourth of all patients undergoing a surgical procedure are taking long-term medications. The issues surrounding the decision to discontinue such medications before surgery and when to reinstitute them are complex. In the preoperative period, it is important to avoid the use of medications that may negatively interact with anesthetic agents. Postoperatively, the concern shifts toward avoiding withdrawal symptoms that may develop and possible progression of the underlying disease if the medications are not restarted in a timely fashion. The potential for decreased gastrointestinal motility in the postoperative patient, which may reduce the efficacy of oral medications, must also be considered. Antihypertensive medications may cause cardiovascular complications, such as hypotension or myocardial ischemia. Psychoactive medications may cause prolonged sedation and withdrawal symptoms may develop. Antithrombotic agents may increase the risks of bleeding during surgery. Several herbal medicines may cause a combination of these effects. CONCLUSION: The decision to withhold and restart medications should be based on available clinical data and expert opinion. Health care professionals should exercise diligence in obtaining an accurate medication history on all preoperative patients and in reviewing the medications in the postoperative orders.

The critical care pharmacist: an essential intensive care practitioner.

Clinical pharmacy services in the critical care setting have expanded dramatically and include assisting physicians in pharmacotherapy decision making, providing pharmacokinetic consultations, monitoring patients for drug efficacy and safety, providing drug information, and offering medical education to physicians, nurses, and patients. Measurable clinical effects of these services include reduced drug errors and adverse drug events, decreased morbidity and mortality rates, and a positive pharmacoeconomic impact by decreasing overall health care costs.

Current and emerging therapy for primary pulmonary hypertension.

OBJECTIVE: To review the epidemiology, pathophysiology, clinical symptoms, and diagnostic workup of primary pulmonary hypertension (PPH) and to discuss the available data on the current and emerging therapies being used to treat this disorder. DATA SOURCES: Primary and review articles were identified with a MEDLINE search (1966-December 2001) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated and all information deemed relevant was included in this review. DATA SYNTHESIS: In the absence of a definable cause, PPH is a disorder classified by a progressive increase in pulmonary vascular resistance and mean pulmonary artery pressure. A relatively rare condition, PPH has an annual incidence of 1-2 cases per million people, slightly higher in women than men. The prognosis is poor, with a mean survival time of 2.8 years after diagnosis if untreated. Vasoconstriction, vascular remodeling, and thrombosis are hallmarks of the disease process. Anticoagulation and vasodilators are the most commonly employed treatment options, showing benefits in clinical outcomes, hemodynamic parameters, and mortality. Several new vasodilators are being evaluated for the treatment of PPH. Bosentan was recently approved as the first oral agent for the treatment of PPH. Iloprost, treprostinil, and beraprost are investigational agents in Phase III studies. CONCLUSIONS: Until additional studies and experience with these agents become available, calcium-channel blockers (CCBs) remain the first option for therapy. For patients not responding to CCBs, therapeutic options will now include epoprostenol and bosentan. Since there are no comparison trials between these 2 agents, therapeutic decisions should be based on patient-specific concerns. Clinical data and experience support the use of epoprostenol; however, in patients at risk or considered unsuitable candidates, bosentan may become a preferred option. Additional studies are warranted to address the potential therapeutic benefits of combination therapy and long-term benefits of agents to treat PPH.