Epinephrine and short-term survival in cardiogenic shock: an individual data meta-analysis of 2583 patients

Objective

Catecholamines have been the mainstay of pharmacological treatment of cardiogenic shock (CS). Recently, use of epinephrine has been associated with detrimental outcomes. In the present study we aimed to evaluate the association between epinephrine use and short-term mortality in all-cause CS patients.

Design

We performed a meta-analysis of individual data with prespecified inclusion criteria: (1) patients in non-surgical CS treated with inotropes and/or vasopressors and (2) at least 15% of patients treated with epinephrine administrated alone or in association with other inotropes/vasopressors. The primary outcome was short-term mortality.

Measurements and results

Fourteen published cohorts and two unpublished data sets were included. We studied 2583 patients. Across all cohorts of patients, the incidence of epinephrine use was 37% (17–76%) and short-term mortality rate was 49% (21–69%). A positive correlation was found between percentages of epinephrine use and short-term mortality in the CS cohort. The risk of death was higher in epinephrine-treated CS patients (OR [CI]?=?3.3 [2.8–3.9]) compared to patients treated with other drug regimens. Adjusted mortality risk remained striking in epinephrine-treated patients (n?=?1227) (adjusted OR?=?4.7 [3.4–6.4]). After propensity score matching, two sets of 338 matched patients were identified and epinephrine use remained associated with a strong detrimental impact on short-term mortality (OR?=?4.2 [3.0–6.0]).

Conclusions

In this very large cohort, epinephrine use for hemodynamic management of CS patients is associated with a threefold increase of risk of death.

     

Migraine induction with calcitonin gene-related peptide in patients from erenumab trials

Background

Migraine prevention with erenumab and migraine induction by calcitonin gene-related peptide (CGRP) both carry notable individual variance. We wanted to explore a possible association between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP.

Methods

Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized cross-over design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess the efficacy of previous antibody treatment. The patients were stratified into groups of high responders and poor responders. Primary outcomes were incidence of migraine-like attacks and area under the curve of headache intensity after infusion of CGRP and placebo. All interviews and experiments were performed in laboratories at the Danish Headache Center, Copenhagen, Denmark.

Results

Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (p?=?0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0–90 min (p?=?0.009), and 2–12 h (p?=?0.014). The median peak headache intensity score was 5 (5–9) after CGRP, compared to 2 (0–4) after placebo (p?=?0.004).

Conclusions

Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. If an association is evident, CGRP provocation could prove a biomarker for predicting antibody treatment efficacy.

Trial registration

Retrospectively registered at clinicaltrials.gov with identifier: NCT03481400.

     

Clinical Presentation and Management of Headache in Pituitary Tumors

Purpose of Review

This article provides an overview of headache in the setting of pituitary adenoma. The purpose of this article is to educate providers on the association, possible pathophysiology, and the clinical presentation of headache in pituitary tumor.

Recent Findings

Recent prospective evaluations indicate that risk factors for development of headache in the setting of pituitary adenoma include highly proliferative tumors, cavernous sinus invasion, and personal or family history of headache. Migraine-like headaches are the predominant presentation. Unilateral headaches are often ipsilateral to the side of cavernous sinus invasion.

Summary

In summary, this paper describes how the size and type of pituitary tumors play an important role in causation of headaches. Pituitary adenoma-associated headache can also mimic primary headache disorders making recognition of a secondary process difficult. Therefore, this paper highlights the association of between trigeminal autonomic cephalgias and pituitary adenomas and urges practitioners to maintain a high index of suspicion when evaluating patients with these uncommon headache presentations. However, on balance, given the prevalence of both primary headache disorders and pituitary adenomas, determining causality can be challenging. A thoughtful and multidisciplinary approach is often the best management strategy, and treatment may require the expertise of multiple specialties including neurology, neurosurgery, and endocrinology.

     

Alcohol Use as a Comorbidity and Precipitant of Primary Headache: Review and Meta-analysis

Purpose of Review

In contrast to well-established relationships between headache and affective disorders, the role of alcohol use in primary headache disorders is less clear. This paper provides a narrative overview of research on alcohol use disorders (AUDs) in primary headache and presents a meta-analysis of the role of alcohol as a trigger (precipitant) of headache.

Recent Findings

The majority of studies on AUDs in headache have failed to find evidence that migraine or tension-type headache (TTH) is associated with increased risk for AUDs or problematic alcohol use. The meta-analysis indicated that 22% (95% CI: 17–29%) of individuals with primary headache endorsed alcohol as a trigger. No differences were found between individuals with migraine (with or without aura) or TTH. Odds of endorsing red wine as a trigger were over 3 times greater than odds of endorsing beer.

Summary

An absence of increased risk for AUDs among those with primary headache may be attributable to alcohol’s role in precipitating headache attacks for some susceptible individuals. Roughly one fifth of headache sufferers believe alcohol precipitates at least some of their attacks. Considerable study heterogeneity limits fine-grained comparisons across studies and suggests needs for more standardized methods for studying alcohol-headache relationships and rigorous experimental designs.

     

Münzkopfschmerz

Background

Subcutaneous peripheral nerve field stimulation (sPNFS) is an established procedure for the treatment of chronic localized neuropathic pain of peripheral origin. The treatment of nummular headache primarily focuses on conservative methods with limited prospects of success. The role of sPNFS in the treatment of nummular headache has not been investigated as yet.

Question

Is the sPNFS an option in the management of nummular headache?

Materials and methods

In addition to a summary of established methods in the treatment of nummular headache, sPNFS as a possible form of therapy is discussed.

Results

A positive effect of sPNFS in terms of the treatment of nummular headache is shown.

Discussion

sPNFS stimulates free subcutaneous nerves and transmits a pleasant form of paraesthesia in the area of pain. If regular conservative therapy has already been exhausted, then sPNFS might be an effective new option in the treatment of nummular headache. sPNFS is a minimally invasive and low-risk procedure. However, the high treatment cost and restrictions regarding fitness to undergo MRI are points of criticism. Further studies are needed to define its potential and role in the treatment of nummular headache.

     

Bath-Related Headache

Purpose of Review

The purpose of this review is to summarize the most up-to-date literature on bath-related headache, a rare disorder.

Recent Findings

Initially described in middle-aged Asian women, it is now reported in a wider demographic. More information is available about the pathophysiology of bath-related headache, including its classification as a subtype of reversible cerebral vasoconstriction syndrome (RCVS). Nimodipine can be effective in patients both with and without vasospasm.

Summary

Bath-related headache is a rare form of thunderclap headache. Although its mechanism is still unclear, it is associated with vasospasm and RCVS. Controlled trials investigating the use of nimodipine and other agents may be useful in furthering our understanding of and treatment of this phenomenon.

     

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants

Background

Cluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms.

Methods

We have performed a genome-wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients with CH and in a control sample of 360 age-matched sigarette smoking healthy individuals, using the Infinium PsychArray (Illumina), which combines common highly-informative genome-wide tag SNPs and exonic SNPs. Genotype data were used to carry out a genome-wide single marker case-control association analysis using common SNPs, and a gene-based association analysis focussing on rare protein altering variants in 745 candidate genes with a putative role in CH.

Results

Although no single variant showed statistically significant association at the genome-wide threshold, we identified an interesting suggestive association (P?=?9.1?×?10^?6) with a common variant of the PACAP receptor gene (ADCYAP1R1). Furthermore, gene-based analysis provided significant evidence of association (P?=?2.5?×?10^?5) for a rare potentially damaging missense variant in the MME gene, encoding for the membrane metallo-endopeptidase neprilysin.

Conclusions

Our study represents the first genome-wide association study of common SNPs and rare exonic variants influencing risk for CH. The most interesting results implicate ADCYAP1R1 and MME gene variants in CH susceptibility and point to a role for genes involved in pain processing. These findings provide new insights into the pathogenesis of CH that need further investigation and replication in larger CH samples.

     

Prevalence of restless legs syndrome in migraine patients with and without aura: a cross-sectional,case-controlled study

Background

Although the comorbidity of migraine and restless legs syndrome (RLS) has been well-documented, the association between RLS and migraine frequency has yet to be elucidated. The present study aims to evaluate the prevalence of RLS among individuals who experience low-frequency, high-frequency, or chronic migraine presenting with and without aura.

Methods

We conducted a cross-sectional, case-controlled study involving 505 participants receiving outpatient headache treatment. Standardized questionnaires were administered to collect information on experiences of migraine, RLS, sleep quality, anxiety, depression, and demographics. Participants were categorized into low-frequency (1–8/month), high-frequency (9–14/month), and chronic (≥15/month) headache groups. RLS was diagnosed according to the criteria outlined by the International RLS Study Group (IRLSSG). The Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS) were used to assess sleep quality and identify symptoms of anxiety and depression. Associations between migraine frequency and RLS prevalence were investigated using multivariate linear and logistic regression.

Results

Univariate analysis revealed an effect of migraine frequency on RLS prevalence (p?=?0.026), though this effect did not persist following adjustment for baseline characteristics (p?=?0.256). The trend was robust in patients whose migraines presented with auras (p _univariate?=?0.002; p _multivariate?=?0.043) but not in those without auras (p _univariate and p _multivariate?>?0.05). Higher anxiety [odds ratio (OR)?=?1.18, p?=?0.019] and sleep disturbance (OR?=?1.17, p?=?0.023) scores were associated with higher RLS prevalence.

Conclusions

Higher migraine frequency correlates with a higher prevalence of RLS, particularly among patients with auras.

     

Treatment Duration,Healthcare Resource Utilization,and Costs Among Chemotherapy-Naïve Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide or Abiraterone Acetate: A Retrospective Claims Analysis

Introduction

Enzalutamide and abiraterone acetate (plus prednisone) are new hormonal treatments for metastatic castration-resistant prostate cancer (mCRPC). This study compared treatment duration, healthcare resource utilization (HRU), and treatment costs for chemotherapy-naïve mCRPC patients treated with enzalutamide or abiraterone acetate in the USA.

Methods

Chemotherapy-naïve mCRPC patients initiating treatment with enzalutamide or abiraterone acetate were identified from administrative claims. Continuous enrollment ≥?6 months before and ≥?3 months after the index date (initiation date of enzalutamide or abiraterone acetate) was required. Treatment duration, all-cause and prostate cancer-related HRU, and costs were estimated during the post-index period. Multivariable analyses compared HRU and costs between cohorts, adjusting for baseline characteristics.

Results

Overall, 920 chemotherapy-naïve patients initiated enzalutamide and 2310 initiated abiraterone acetate (median follow-up, 10.7 and 13.5 months, respectively). More enzalutamide-treated patients had corticosteroid-sensitive comorbidities at baseline. Treatment duration was longer with enzalutamide versus abiraterone acetate (median, 10.7 vs. 8.8 months; P?=?0.008). Enzalutamide was associated with fewer all-cause inpatient admissions [adjusted incidence rate ratio (95% confidence interval) 0.87 (0.76, 0.99)], days of hospitalization [0.84 (0.70, 1.02)], and outpatient visits [0.94 (0.90, 0.98)], and fewer prostate cancer-related outpatient visits [0.92 (0.87, 0.96)] compared with abiraterone acetate. Enzalutamide was also associated with lower prostate cancer-related inpatient and emergency department costs [adjusted differences, $122 (P?=?0.024) and $28 (P?=?0.009), respectively].

Conclusion

Chemotherapy-naïve mCRPC patients treated with enzalutamide versus abiraterone acetate had longer treatment duration and incurred lower HRU and prostate cancer-related inpatient and emergency department costs.

Funding

Astellas Pharma Inc.

     

Earlier Versus Later Augmentation with an Antipsychotic Medication in Patients with Major Depressive Disorder Demonstrating Inadequate Efficacy in Response to Antidepressants: A Retrospective Analysis of US Claims Data

Introduction

There is little evidence regarding the most effective timing of augmentation of antidepressants (AD) with antipsychotics (AP) in patients with major depressive disorder (MDD) who inadequately respond to first-line AD (inadequate responders). The study’s objective was to understand the association between timing of augmentation of AD with AP and overall healthcare costs in inadequate responders.

Methods

Using the Truven Health MarketScan^® Medicaid, Commercial, and Medicare Supplemental databases (7/1/09–12/31/16), we identified adult inadequate responders if they had one of the following indicating incomplete response to initial AD: psychiatric hospitalization or emergency department (ED) visit, initiating psychotherapy, or switching to or adding on a different AD. Two mutually exclusive cohorts were identified on the basis of time from first qualifying event date to first date of augmentation with an AP (index date): 0–6 months (early add-on) and 7–12 months (late add-on). Patients were further required to be continuously enrolled 1 year before (baseline) and 1 year after (follow-up) index date. Patients with schizophrenia or bipolar disorder diagnoses were excluded. General linear regression was used to estimate adjusted healthcare costs in the early versus late add-on cohort, controlling for baseline demographic and clinical characteristics, insurance type, medications, and ED visits or hospitalizations.

Results

Of the 6935 identified inadequate responders, 68.7% started an AP early and 31.3% late. At baseline, before AP augmentation, patients in the early add-on cohort had higher psychiatric comorbid disease burden (47.3% vs. 42.5%; p?<?0.001) and higher inpatient utilization [mean (SD) 0.41 (0.72) vs. 0.27 (0.67); p?<?0.001] than in late add-on cohort. During follow-up, the adjusted total all-cause healthcare cost was significantly lower in the early vs. late add-on cohort ($18,864 vs. $20,452; p?=?0.046).

Conclusion

Findings of this real-world study suggest that, in patients with MDD who inadequately responded to first-line AD treatment, adding an AP earlier reduces overall healthcare costs.

Funding

Otsuka Pharmaceutical Development and Commercialization, Inc. and Lundbeck.

     

Bifrontal brain abscesses secondary to orbital cellulitis and sinusitis extension

Background

Intracranial abscesses are rare and life-threatening conditions that typically originate from direct extension from nearby structures, hematogenous dissemination or following penetrating cerebral trauma or neurosurgery.

Findings

A 36-year-old male presented to our emergency department with complaints of left eye swelling, headache and drowsiness. On physical exam, the patient was febrile and his left upper eyelid was markedly swollen with fluctuance and drainage. Maxillofacial computed tomography was obtained to evaluate for orbital pathology but revealed bifrontal brain abscesses.

Conclusions

Brain abscesses should be considered in the differential diagnosis for patients who present with the classic triad of headache, fever and neurological deficit.

     

Effects of adjuvant chemotherapy on recurrence,survival, and quality of life in stage II colon cancer patients: a 24-month follow-up

Purpose

The purpose of this cohort study was to investigate the association of adjuvant chemotherapy with quality of life (QoL), survival, and recurrence over the 24 months following diagnosis in stage II colon cancer patients.

Methods

Overall, 453 patients were recruited from North Carolina from 2009 to 2011 and interviewed with a closed-ended survey detailing quality of life, health behaviors, treatment, and cancer recurrence at three times points: diagnosis, 12-, and 24-months post-diagnosis; mortality was obtained via the National Death Index.

Results

In sum, 265 patients received chemotherapy. Receipt of chemotherapy exhibited an inverse association with total Functional Assessment of Cancer Treatment (FACT)-General (P?<?0.01), FACT-Colorectal (P?<?0.01), physical (P?<?0.01), emotional (P?=?0.02), and functional (P?<?0.01) well-being; the inverse association between receiving chemotherapy and emotional well-being persisted for Caucasians but not African Americans (P _interaction?=?0.049). Those who received chemotherapy demonstrated significantly higher odds of cancer recurrence (odds ratio (OR) 2.74; 95 % confidence interval (CI) 1.18, 6.35) and all-cause mortality (OR: 1.95; 95 % CI: 1.05, 3.62).

Conclusions

In this study, stage II colon cancer patients who received chemotherapy treatment were more likely to have poor QoL, recurrence, and all-cause mortality after 24 months compared to those who did not receive chemotherapy. Future research focusing on subtypes of chemotherapy treatment, as well as a longer follow-up period, is needed.

     

Pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection

Purpose

Loss of colonization resistance within the gastrointestinal microbiome facilitates the expansion of pathogens and has been associated with death and infection in select populations. We tested whether gut microbiome features at the time of intensive care unit (ICU) admission predict death or infection.

Methods

This was a prospective cohort study of medical ICU adults. Rectal surveillance swabs were performed at admission, selectively cultured for vancomycin-resistant Enterococcus (VRE), and assessed using 16S rRNA gene sequencing. Patients were followed for 30 days for death or culture-proven bacterial infection.

Results

Of 301 patients, 123 (41%) developed culture-proven infections and 76 (25%) died. Fecal biodiversity (Shannon index) did not differ based on death or infection (p?=?0.49). The presence of specific pathogens at ICU admission was associated with subsequent infection with the same organism for Escherichia coli, Pseudomonas spp., Klebsiella spp., and Clostridium difficile, and VRE at admission was associated with subsequent Enterococcus infection. In a multivariable model adjusting for severity of illness, VRE colonization and Enterococcus domination (≥?30% 16S reads) were both associated with death or all-cause infection (aHR 1.46, 95% CI 1.06–2.00 and aHR 1.47, 95% CI 1.00–2.19, respectively); among patients without VRE colonization, Enterococcus domination was associated with excess risk of death or infection (aHR 2.13, 95% CI 1.06–4.29).

Conclusions

Enterococcus status at ICU admission was associated with risk for death or all-cause infection, and rectal carriage of common ICU pathogens predicted specific infections. The gastrointestinal microbiome may have a role in risk stratification and early diagnosis of ICU infections.

     

Pharmacotherapy Choice Is Associated with 2-Year Mortality for Patients with Heart Failure and Reduced Ejection Fraction

Introduction

Factors associated with mortality for patients with heart failure and reduced ejection fraction (HFrEF) are known; however, the association between initial pharmacotherapy (IPT) and mortality is unclear in real-world settings.

Methods

Using a retrospective design and claims database, 14,359 Medicare patients with HFrEF from August 2010 to July 2015 were identified. Index date was first HF claim. IPT was mono- or combo-angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), beta-blocker (BB), hydralazine–nitrate (HN), and aldosterone antagonist (AA) within 1 year post-index. A multivariable time-dependent Cox model estimated associations between IPT and 2-year all-cause mortality.

Results

Patients’ median age was 76 (70–82) years; 45.1% were female. Within 1 month post-index, 61.4% had IPT, 6.1% started after the first month, and 32.4% had no IPT in the first year. Of IPTs, 47.5% were mono-vasodilators (ACEI, ARB or HN), 23.3% mono-vasodilator + BB, 16.9% mono-BB, and 3.5% triple therapy [(ACEI or ARB) + BB + (HN or AA)]. Two-year mortality rate was 27.9%. Compared to mono-vasodilator therapy, patients initiating triple therapy had 29.3% lower risk of 2-year mortality; those on mono-BB or no IPT had higher mortality risk.

Conclusion

IPT was associated with decreased 2-year mortality risk. Timely consideration of triple IPT therapies may be warranted once HFrEF diagnosis is confirmed.

Funding

Novartis Pharmaceuticals Corp. located in East Hanover, NJ, USA.

     

Factors Associated with Sport-Related Post-concussion Headache and Opportunities for Treatment

Purpose of Review

The purpose of this review is to (1) describe factors both pre- and post-injury that are associated with post-concussion headache, (2) describe the influence of post-concussion headache on recovery following concussion, and (3) provide potential post-concussion treatment options that may reduce the burden of headache, as well as other symptoms to facilitate recovery.

Recent Findings

Various factors may be associated with post-concussion headache presentation. These may include pre-injury or historical factors such as sex, family and self-history of headache and migraine, concussion history, and mood disorders. In addition, post-injury presentation factors for consideration may include injury mechanism, symptom clusters, cervicogenic dysfunction, and post-concussion physiologic dysfunction. Despite this complex interplay of factors, many treatment options may improve headache symptoms and recovery post-concussion including rehabilitation programs focusing on deficits such as visual-vestibular dysfunction, sub-symptom threshold exercise, and potential pharmacological interventions.

Summary

Concussion is a complex injury that results in a variety of sequelae with headache being one of the most common. Understanding factors related to post-concussion headache presentation and the available options for treatment may improve patient care and outcomes post-concussion.

     

Headache in Neuromyelitis Optica

Purpose of Review

Neuromyelitis optica (NMO) classically features a clinical presentation that includes longitudinally extensive transverse myelitis and optic neuritis. However, many other pathognomonic phenomena have more recently been described in patients diagnosed with NMO, including intractable hiccups, vomiting, and painful tonic spasms, but less has been reported regarding the relationship between NMO and headache. Though headache is well established as both a symptom and comorbidity of multiple sclerosis (MS), it has been much less described thus far in the NMO literature and warrants more careful evaluation. Many questions remain unanswered about the relationship between NMO and headache, including headache prevalence in certain groups, distribution of primary and symptomatic headache disorders that are seen most frequently and the specific neuroimaging findings that are associated with an increased risk of headache.

Recent Findings

Various types of headache, such as cervicogenic headache and trigeminal autonomic cephalalgia-like headache, have been reported as the initial clinical presentation of NMO. Other publications have emphasized the association of NMO and other etiologies of headache, such as trigeminal neuralgia, PRES, and preeclampsia. Certain MR imaging findings such as medullary lesions in patients with NMO have also been associated with headache.

Summary

The link between headache and NMO is evident not only in limited case reports and clinical studies but also with both MR imaging and even with some potential common underlying biomarkers such as pentraxin-3 and interleukin-6. Developing a further understanding in the association between these two diseases may lead to better management of headache in patients with NMO and potentially lead to earlier diagnosis of NMO in whom headache may serve as an initial presenting symptom and may even herald a disease exacerbation.

     

Impact of a Health Management Program on Healthcare Outcomes among Patients on Augmentation Therapy for Alpha 1-Antitrypsin Deficiency: An Insurance Claims Analysis

Introduction

Alpha 1-antitrypsin deficiency (AATD) is a genetic disorder which reduces serum alpha 1-antitrypsin (AAT or alpha1-proteinase inhibitor, A1PI) and increases the risk of chronic obstructive pulmonary disease (COPD). Management strategies include intravenous A1PI augmentation, and, in some cases, a health management program (Prolastin Direct^®; PD).

Objectives

This study compared clinical and economic outcomes between patients with and without PD program participation.

Methods

This retrospective study included commercial and Medicare Advantage health insurance plan members with ≥?1 claim with diagnosis codes for COPD and ≥?1 medical or pharmacy claim including A1PI (on index date). Outcomes were compared between patients receiving only Prolastin^® or Prolastin^®-C (PD cohort) and patients who received a different brand without PD (Comparator cohort). Demographic and clinical characteristics were captured during 6 months pre-index. Post-index exacerbation episodes and healthcare utilization and costs were compared between cohorts.

Results

The study sample comprised 445 patients (n?=?213 in PD cohort; n?=?232 in Comparator cohort), with a mean age 55.5 years, 50.8% male, and 78.9% commercially insured. The average follow-up was 822 days (2.25 years), and the average time on A1PI was 747 days (2.04 years). Few differences were observed in demographic or clinical characteristics. Adjusting for differences in patient characteristics, the rate of severe exacerbation episodes was reduced by 36.1% in the PD cohort. Adjusted total annual all-cause costs were 11.4% lower, and adjusted mean respiratory-related costs were 10.6% lower in the PD cohort than the Comparator cohort. Annual savings in all-cause total costs in the PD cohort relative to the Comparator cohort was US$25,529 per patient, largely due to significantly fewer and shorter hospitalizations.

Conclusions

These results suggest that comprehensive health management services may improve both clinical and economic outcomes among patients with COPD and AATD who receive augmentation therapy.

Funding

Grifols Shared Services of North America, Inc.