Slow Infusion Rate Research Articles

Allergic reactions to enzyme replacement therapy in children with lysosomal storage diseases and their management.

Human recombinant enzyme replacement therapy, given to compensate for genetic enzyme deficiency in lysosomal storage diseases, delays the progression of the disease and improves the quality of life. However, enzyme replacement therapy may cause hypersensitivity reactions. Within the scope of this research, we aimed to elucidate the frequency and clinical features of hypersensitivity reactions against enzyme replacement therapy in children with lysosomal storage diseases and clarify the management of these reactions. Medical records of pediatric patients with lysosomal storage disease and receiving enzyme replacement therapy were retrospectively reviewed, and patients who experienced allergic reactions were included in the study. The demographic characteristics of the patients, their diagnosis, the responsible enzyme, the time at which the reaction started and at what dose, the signs and symptoms associated with the reaction, diagnostic tests, the management of the reaction, and the protocol applied for the maintenance of enzyme replacement therapy after the reaction were recorded. Hypersensitivity reactions developed in 18 of 71 patients (25.3 %) who received enzyme replacement therapy. The most common cutaneous findings were observed. Anaphylaxis developed in 6 of 18 patients. Patients who experienced recurrent hypersensitivity reactions with premedication or a slower infusion rate, those with positive skin test results, and patients who developed anaphylaxis were given enzyme replacement therapy with desensitization. HSR may develop during enzyme replacement therapy, which are vital in lysosomal storage diseases, and discontinuation of enzyme replacement therapy is a significant loss for patients with metabolic disorders. These reactions can be treated with premedication and long-term infusions, but some patients may require desensitization protocols for continued treatment.

Home parenteral nutrition, sleep patterns, and depressive symptoms: Secondary analysis of cross-sectional data.

Patients receiving home parenteral nutrition (HPN) are known to experience psychological distress and have profoundly disrupted sleep. The aim of this analysis was to examine the relationship between sleep patterns with depressive symptoms and HPN characteristics. The study was a secondary analysis of cross-sectional data examining sleep patterns using subjective and objective measures. Sleep was assessed by surveys and 7-day actigraphy. The Patient Health Questionnaire-8 was used to evaluate depressive symptoms. Participants provided information on HPN. Spearman correlations were calculated between sleep measures with depressive symptoms and HPN characteristics. Correlations were further examined in multivariable linear regression models. Thirty-two adults (age = 53 years; 75% female; 94% White) were included. Lower sleep quality (r = 0.54-0.60; P < 0.001) and later sleep timing (r = -0.35; P = 0.049) were correlated with higher depressive symptoms. Sleep patterns were also correlated with several HPN characteristics (r = -0.47 to 0.51). In linear regression models, rate of infusion was associated with sleep duration (β = -0.004 [0.002] h; P = 0.046) in which each 100 mL/h was associated with 24-min shorter duration. Higher total energy was associated with lower sleep quality (β = 0.0004 [0.0002] log-unit; P = 0.042), and higher volume was associated with longer sleep onset latency (β = 0.0006 [0.0003] log-min; P = 0.049). We provide evidence supporting the link between poor and later sleep with higher depressive symptoms and identify potentially modifiable infusion characteristics (notably, slower rate of infusion and lower total energy and volume) that, on further verification, may support sleep among those receiving HPN.

Two versus Three Infusion Regimens of N-Acetylcysteine for Acetaminophen Overdose.

Acetaminophen overdose is a common clinical condition, often leading to liver toxicity. Current treatments involve the three-infusion N-Acetylcysteine (NAC) regimen (FDA-labeled), which may be complex, time-consuming, and need to be changed. An alternative uses two infusions instead, which offers possible advantages regarding simplicity and administration errors. This study sought to compare the respective efficacies and safety outcomes when treating acute acetaminophen overdose among children and adolescents. At Montreal Children's Hospital, a retrospective study was conducted comparing pre-2003 FDA-labelled three-infusion NAC therapy with a two-infusion regimen. Information was collected regarding patient demographics, NAC administration details, errors, rates of hepatotoxicity, and adverse reactions, and the statistical test Chi-square test was employed to obtain the results. A total of 126 patients met the inclusion criteria. Of these patients, 65 received a two-infusion regimen, and 61 patients received the FDA-labeled regimen. The two-infusion group experienced significantly fewer administration errors (4 errors vs. 23 errors; p < 0.001), while the rates of hepatotoxicity between them were similar. There were no instances of liver transplantation or mortality due to either regimen. Adverse reactions occurred equally frequently between both regimens with no discernible difference-the meantime to administer NAC was 9 h for the two-infusion regimen and 8.5 h for FDA-labeled regimen groups, respectively. Three cases of hepatitis were successfully treated with timely NAC therapy, and no liver transplantation or mortality occurred. Adverse reactions, including anaphylactoid reactions, were observed in both groups but were resolved when temporarily stopped and restarted at a slower infusion rate. The two-infusion NAC regimen proved similar efficacy at protecting liver damage and improving patient outcomes compared to its FDA-labeled three-stage counterpart, with significantly fewer administration errors for this version of NAC treatment, suggesting potential advantages in terms of safety and simplicity. Future research should investigate larger cohorts and more variables to validate these results further and optimize the management of acetaminophen overdose cases; further investigation should focus on dosing strategies, personalized approaches, and long-term patient care in this context.

Management of nausea and vomiting (N/V) following first-line (1L) zolbetuximab + chemotherapy treatment in claudin-18.2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Analysis from the phase 3 SPOTLIGHT and GLOW studies.

372 Background: The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies showed clinically meaningful, statistically significant improvement in PFS and OS using 1L zolbetuximab + chemotherapy vs placebo (PBO) + chemotherapy in patients (pts) with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. N/V were the most common treatment-emergent adverse events (TEAEs) reported in the zolbetuximab arm of these studies. We report an analysis of the incidence and management of N/V in SPOTLIGHT and GLOW. Methods: In SPOTLIGHT, pts (N = 565) were randomized 1:1 to zolbetuximab + mFOLFOX6 vs PBO + mFOLFOX6. In GLOW, pts (N = 507) were randomized 1:1 to zolbetuximab + CAPOX vs PBO + CAPOX. In both studies, neurokinin-1 receptor blockers (NK-1), selective serotonin receptor blockers (5-HT3), and other prophylactic antiemetic regimens were recommended to prevent and mitigate N/V per institutional care and guidelines. Results: A total of 279 pts in SPOTLIGHT and 253 pts in GLOW received zolbetuximab + chemotherapy. In SPOTLIGHT and GLOW combined, nausea occurred in 58% vs 18% of pts, and vomiting occurred in 43% vs 15% of pts in the first vs second zolbetuximab infusions, respectively; lower incidences of N/V were observed thereafter. During the first zolbetuximab infusion, the first episode of N/V occurred within 1 hour (median time, 48.0 min in SPOTLIGHT and 56.5 min in GLOW). Antiemetic usage and associated N/V rates are presented in the Table. The 96 pts in SPOTLIGHT and 52 pts in GLOW who had infusion modifications in cycle 1 due to TEAEs had numerically higher infusion rates than pts without infusion modifications; 85% of these modifications in SPOTLIGHT and 79% in GLOW were due to N/V. Zolbetuximab was discontinued within the first 9 weeks in 11 and 7 pts in SPOTLIGHT and 6 and 4 pts in GLOW due to nausea or vomiting, respectively. Conclusions: In SPOTLIGHT and GLOW, slower infusion rate and use of antiemetic combinations may have helped to mitigate N/V. These strategies will be important to support continued treatment and allow pts to achieve maximum clinical benefit with zolbetuximab + chemotherapy. Clinical trial information: NCT03504397 and NCT03653507 . [Table: see text]

Relationship between the rate of fluid resuscitation and acute kidney injury: A retrospective cohort study.

Septic shock is the leading cause of acute kidney injury (AKI) in critically ill patients. The foundation of early septic shock management includes early fluid resuscitation, but the association between fluid resuscitation rates and kidney outcomes remains unclear. This investigation examines the association between fluid resuscitation rate and AKI recovery. In the medical intensive care unit of Mayo Clinic Rochester, adult patients with AKI and septic shock were retrospectively studied from January 1, 2006 to May 31, 2018. The surviving sepsis campaign recommends an initial fluid bolus of 30 ml/kg for sepsis resuscitation. The cohort of patients was divided into three groups based on the average fluid resuscitation time (<1 h, 1.1-3 h, >3 h) and the corresponding fluid rate ≥0.5, 0.17-0.49, and <0.17 ml/kg/min, respectively. The primary outcome was the recovery of AKI on day 7. To account for potential confounders, multivariable regression analyses were conducted. After meeting the eligibility, 597 patients were included in the analysis. The AKI recovery was considerably different among the groups (P = 0.006). Patients in group 1 who received fluid resuscitation faster had a higher rate of AKI recovery (53%) compared to group 2 and group 3 (50% and 37.8%). In septic shock patients with AKI, a higher fluid resuscitation rate of 30 ml/kg IV fluids within the 1st-h sepsis diagnosis (i.e., >0.50 ml/kg/min) lead to higher AKI recovery compared with slower infusion rates.

High-Dose Intravenous Iron with Either Ferric Carboxymaltose or Ferric Derisomaltose: A Benefit-Risk Assessment.

The intravenous iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) offer the possibility of administering a large amount of iron in one infusion. This results in faster correction of anemia and the formulations being better tolerated than oral iron formulations. This triad of logistic advantages, improved patient convenience, and fast correction of anemia explains the fact that intravenous iron formulations nowadays are frequently prescribed worldwide in the treatment of iron deficiency anemia. However, these formulations may result in hypophosphatemia by inducing a strong increase in active fibroblast growth factor-23 (FGF-23), a hormone that stimulates renal phosphate excretion. This effect is much more pronounced with FCM than with FDI, and therefore the risk of developing hypophosphatemia is remarkably higher with FCM than with FDI. Repeated use of FCM may result in severe osteomalacia, which is characterized by bone pain, Looser zones (pseudofractures), and low-trauma fractures. Intravenous iron preparations are also associated with other adverse effects, of which hypersensitivity reactions are the most important and are usually the result of a non-allergic complement activation on nanoparticles of free labile iron—Complement Activation-Related Pseudo-Allergy (CARPA). The risk on these hypersensitivity reactions can be reduced by choosing a slow infusion rate. Severe hypersensitivity reactions were reported in < 1% of prospective trials and the incidence seems comparable between the two formulations. A practical guideline has been developed based on baseline serum phosphate concentrations and predisposing risk factors, derived from published cases and risk factor analyses from trials, in order to establish the safe use of these formulations.

Tolerance of the mRNA COVID-19 vaccines in patients with reported taxane reactions

Tolerance of the mRNA COVID-19 vaccines in patients with reported taxane reactions

Real world risk of infusion reactions and effectiveness of front-line obinutuzumab plus chlorambucil compared with other frontline treatments for chronic lymphocytic leukemia

BackgroundChronic lymphocytic leukemia (CLL) is the most common type of leukemia in North America. Previous studies have shown improved progression free survival (PFS) and response rates in unfit patients treated with obinutuzumab compared to other regimens. The aim of this study was to evaluate the obinutuzumab-chlorambucil regimen in the context of historical treatments and first-dose infusion reactions at CancerCare Manitoba (CCMB).MethodsA retrospective chart review was conducted for patients treated with obinutuzumab from January 1, 2014 to December 31, 2017 at CCMB. A minimum data set was extracted for patients treated with other front-line therapies. Descriptive statistics were used to evaluate patient demographics, toxicity, duration and dosing of obinutuzumab treatment. Kaplan–Meier curves were used to evaluate time-to-next-treatment (TTNT), overall survival (OS) and PFS for patients treated with obinutuzumab. A multivariable logistic regression model was used to investigate associations between infusion related reactions (IRRs) and age at treatment, pre-treatment lymphocyte count, cumulative illness rating scale (CIRS) and receipt of prior chemotherapy.ResultsForty seven percent of patients receiving frontline therapy received chlorambucil and obinutuzumab. Sixty-seven patients were treated with obinutuzumab and consisted of 36 males (53.7%) and 31 females (46.3%) with 29 patients (43.3%) over age 75 years. Rates of grade 3 and 4 obinutuzumab IRRs were lower (6%) compared to the CLL11 clinical trial (20%) due to local practices including slower infusion rates and using chlorambucil before starting obinutuzumab treatment. Many patients had difficulty tolerating the full dosage of chlorambucil. Only 26 patients (38.8%) had their dose of chlorambucil escalated to the full dose of 0.5 mg/kg. In addition, only 18 patients (26.9%) received all doses of obinutuzumab and all 12 doses of chlorambucil.ConclusionsIn summary, first dose infusion reactions with obinutuzumab can be markedly reduced by using chlorambucil to decrease the lymphocyte count before obinutuzumab and by using a very slow initial obinutuzumab infusion rate. Modifications in chlorambucil dosing and obinutuzumab administration can improve tolerance without significant loss in efficacy.

Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones, Vancomycin, Tetracyclines, and Macrolides.

While fluoroquinolones, vancomycin, macrolides, and tetracyclines are generally safe antibiotics, they can induce both immediate and delayed hypersensitivity reactions (HSRs). Historically, less has been published on allergies to these antibiotics compared to beta lactams, but the prevalence of non-beta lactam HSRs is increasing. To fluoroquinolones, immediate HSRs are more common than delayed reactions. Both IgE and non-IgE mechanisms, such as the mast cell receptor Mas-related G protein-coupled receptor X2 (MRGPRX2), have been implicated in fluoroquinolone-induced anaphylaxis. Skin testing for fluoroquinolones is controversial, and the gold standard for diagnosis is a graded dose challenge. To vancomycin, the most common reaction is vancomycin infusion reaction (previously called "red man syndrome"), which is caused by infusion rate-dependent direct mast cell degranulation. Severity can range from flushing and pruritis to angioedema, bronchospasm, and hypotension that mimic type I HSRs. MRGPRX2 has been implicated in vancomycin infusion reactions. IgE-mediated HSRs to vancomycin are rare. Vancomycin skin testing yields high false positive rates. Thus, direct provocation challenge with slower infusion rate and/or antihistamine pre-treatment is preferred if symptoms are mild to moderate, and desensitization can be considered if symptoms are severe. To tetracyclines, non-IgE-mediated and delayed HSRs predominate with cutaneous reactions being the most common. There is no standardized skin testing for tetracyclines, and avoidance is generally recommended after a severe reaction because of the paucity of data for testing. Graded dose challenges and desensitizations can be considered for alternative or index tetracyclines if there are no alternatives. With macrolides, urticaria/angioedema is the most common immediate HSR, and rash is the most common delayed HSR. The predictive value for skin testing to macrolides is similarly poorly defined. In general, HSRs to fluroquinolones, vancomycin, macrolides, and tetracyclines are challenging to diagnose given the lack of validated skin testing and in vitro testing. Direct provocation challenge remains the gold standard for diagnosis, but the benefits of confirming an allergy may not outweigh the risk of a severe reaction. Skin testing, direct provocation challenge, and/or desensitization to the index non-beta lactam antibiotic or alternatives in its class may be reasonable approaches depending on the clinical context and patient preferences.

Crizanlizumab-Associated Painful Febrile Reaction in Sickle Cell Disease Patients

Background: P-selectin expressed on endothelium and platelets has been implicated in the pathophysiology of vaso-occlusive crises (VOCs) in sickle cell disease (SCD) patients. Crizanlizumab is a humanized monoclonal anti-P-selectin antibody approved by the FDA to reduce the frequency of VOCs. While severe adverse events (AEs) are rare, over 80% of patients most commonly have headache, back pain, nausea, or arthralgia; infusion-related reactions occurred in 3% according to the package insert. We report on 2 patients whose crizanlizumab-associated reactions help shed light on how to manage such events and possible mechanisms.Case reports: Case 1, a 48-year-old woman with hemoglobin SC disease, history of left shoulder replacement due to avascular necrosis and left knee avascular necrosis, pending surgical replacement. Given her frequent pain episodes, she was initiated on crizanlizumab after being intolerant to hydroxyurea (watery diarrhea). She received the first dose of crizanlizumab uneventfully, but at the end of her second infusion, she developed acute bilateral groin pain that radiated to both legs. She was eventually admitted to the hospital with a fever of 38-39°C without evidence of infection. She also received one unit of RBC transfusion for a drop in Hct from 32% to 25%. For her third infusion, we premedicated her with acetaminophen 650mg, diphenhydramine 50mg, ketorolac 1g along with concurrent IV hydration. She tolerated an initial infusion at 20ml/h for the first 15 minutes after which we ramped it up to the regular rate of 200ml/h. Within minutes of that rate increase, the patient developed chest pain and dyspnea, so infusion was stopped immediately. Blood samples taken right after the event revealed tryptase and IgE levels within normal limits, and she chose to discontinue the medication.Case 2, a 20-year-old woman with sickle cell anemia with frequent painful episodes despite hydroxyurea at 25mg/kg/day. The patient preferred to start crizanlizumab over increasing oral medication. She reported having had fever and chills at home after her first crizanlizumab infusion and improved with acetaminophen. About 10 minutes into her second infusion, she developed acute severe migratory pain in her back, moving to her lower limbs, associated with tachycardia. Infusion was immediately discontinued, and she was medicated with diphenhydramine 25mg and methylprednisolone 125mg with no improvement. She progressed with abdominal pain moving into her arms and needed meperidine 25mg and hydromorphone 1mg to achieve pain resolution. She completed the infusion successfully at 50% reduced rate but still reported subjective high fevers and chills again the next day, medicated with acetaminophen. She continues monthly infusions with a slower rate.Discussion: As of October 2020, Novartis (manufacturer of crizanlizumab) informed that, out of 3,500 patients, there have been 22 postmarketing reports of severe pain during or within 24 hours of the infusion. Seven cases reported complications, all of which resolved. Immediate hypersensitivity reactions to monoclonal antibodies can be a cytokine release syndrome, IgE-mediated, or IgG-mediated. One case report has suggested this may be a complement activation-related pseudoallergy (CARPA) as sC5b-9 was mildly elevated in a 17-year-old male patient who developed sudden and severe pain in his back, legs and head within 10 minutes of the infusion, despite having been premedicated with acetaminophen, later developing a fever and need for admission. Differently from that case, our patients developed severe pain with a second exposure of the drug, arguing in favor of an antibody-mediated process. We did not find evidence of mast cell activation or increased IgE production in our patient who needed to discontinue the medication. We therefore hypothesize that crizanlizumab-associated painful febrile reaction may be IgG-mediated. Premedication in our experience was unsuccessful, and symptomatic treatment with acetaminophen was appropriate, but slower infusion rates may prove useful for some patients.Conclusion: While rare, crizanlizumab-associated painful febrile reactions may be observed after a first uneventful infusion and are possibly IgG-mediated. Patients experiencing this reaction may require symptomatic treatment with acetaminophen despite premedication and can be tried on slower infusion rates. DisclosuresFertrin: Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

The Optimal Cell Salvage Settings to Maximize Hematocrit and Minimize Potassium Using the Cobe BRAT2 Autologous Blood Recovery Unit

The objective was to determine the optimal cell saver device settings (infusion rate and wash rate) at which hematocrit is preserved and potassium and lactate are removed from banked red blood cells (RBC). Red cells were washed using the Cobe BRAT 2 Autologous Blood Recovery Unit and sampled for electrolyte composition and hematocrit pre- and postwash. This was a single-center study. Red cells were washed using six infusion rates (100-1,000 mL/min) and six wash rates (100-1,000 mL/min) for a total of 36 combinations. Hematocrit, potassium, glucose, and lactate were evaluated before and after washing. At wash rates ≤400 mL/min, hematocrit increased independent of infusion rate. At wash rates ≥400 mL/min, slower infusion rates were associated with higher hematocrit compared to faster infusion rates (p < 0.0001 for a wash rate 400-800 mL/min, p < 0.0005 for a wash rate 1,000 mL/min). Maximal wash speeds were associated with decreasing hematocrit. Infusion and wash rate were both independent predictors of potassium change; slower rates were associated with a larger decrease in potassium. Glucose decreased proportionally as infusion and wash rate decreased. Lactate did not show an association with either infusion or wash rate. Red-cell washing produces higher hematocrit and lower potassium as infusion rate and wash rate decrease. A 340-mL unit of RBC can be processed in 4.26 minutes without loss of hematocrit or an increase in potassium when both infusion and wash rates are set to 400 mL/min.

Pretreatment with dexmedetomidine and magnesium sulphate in prevention of etomidate induced myoclonus - A double blinded randomised controlled trial.

Pretreatment with dexmedetomidine and magnesium sulphate in prevention of etomidate induced myoclonus - A double blinded randomised controlled trial.

Pegaspargase Re-Challenge after Grade 2 Hypersensitivity Reaction in Childhood Acute Lymphoblastic Leukemia: Results from DFCI 16-001

Introduction: Hypersensitivity reactions with asparaginase occur frequently in pediatric patients (pts) with acute lymphoblastic leukemia (ALL). The standard approach for pts with reaction to E.coli-derived asparaginase is to switch to Erwinia asparaginase, given concern that clinical reactions reflect presence of neutralizing antibodies; however, Erwinia requires more frequent dosing and is often unavailable. Therapeutic drug monitoring allows for discrimination between pts with pegaspargase hypersensitivity who have sub-therapeutic asparaginase activity and those still able to derive therapeutic benefit from pegaspargase. We prospectively piloted re-challenging pts with pegaspargase after initial Grade 2 hypersensitivity to this agent, with premedication at re-challenge and assessment of serum asparaginase activity (SAA). Methods: Pts aged 1 to &amp;lt; 22 years with newly diagnosed ALL were eligible for DFCI 16-001. Pts received 1 dose of intravenous pegaspargase during Induction, and every 2 weeks for 15 total doses in Post-Induction phases, without routine premedication. Pts were monitored during/after pegaspargase for allergy, with CTCAE version 4.0 event grading. Those with ≥Grade 3 allergy discontinued pegaspargase and were switched to Erwinia. Those with Grade 2 allergic reaction were eligible for pegaspargase re-challenge with pre-medication (acetaminophen, diphenhydramine, and hydrocortisone, or per institutional standard) and slower infusion rate. If &amp;lt; 50% of the intended dose had been administered when reaction occurred, re-challenge was within 1-7 days of initial reaction. If ≥ 50% of the intended dose had been given, re-challenge was at next planned pegaspargase dose. SAA was measured 1-hour, 7-days, and 14-days after the re-challenge infusion (if dose completed). If 1-hour or 7-day level ≥ 0.1 IU/mL, and 14-day level ≥ 0.025 IU/mL, SAA was considered adequate, and the pt continued to receive pegaspargase with premedication. Pts with an inadequate SAA level, or with new ≥ Grade 2 allergic reaction with the re-challenge dose were considered to have failed re-challenge and were changed to Erwinia (or enrolled on a clinical trial of recombinant crisantaspase, an alternative Erwinia preparation). Results: Between 3/2017- 7/2020, 317 eligible pts enrolled. Overall, 81 of 299 (27%) total evaluable pts experienced a first allergic reaction to pegaspargase, 68 pts with Grade 2 reaction, 13 with Grade ≥3. During Induction, 17 of 299 (6%) evaluable pts had allergic reaction to pegaspargase; all Grade 2. Of the 17 Grade 2 reactions, 13 pts (76%) underwent re-challenge in Induction, 9 (69%) re-challenges successful and 4 failed. Post-Induction, 64 of 241 evaluable pts (27%) had a first allergic reaction; 51 Grade 2 and 13 Grade ≥3. Thirty-six of 51 (71%) pts with Grade 2 allergy during Post-Induction underwent re-challenge, as did 1 additional pt with allergy during Induction who was re-challenged with first Post-Induction pegaspargase dose (per protocol guideline, due to receiving ≥50% of Induction dose). Among these re-challenges, 16 were successful, 21 failed. Overall, 25 of 50 (50%) pts who were re-challenged after Grade 2 reaction had a successful challenge and were able to continue pegaspargase. Among the 25 pts with failed re-challenge, 6 pts (24%) had inadequate SAA alone as cause of failure, 17 pts (68%) had an allergic reaction with the re-challenge dose, and 2 (8%) additional patients had both allergic reaction and documented inadequate SAA. Three pts who were successfully re-challenged had a subsequent allergic reaction to pegaspargase. Among the 22 pts who experienced another allergic reaction with pegaspargase (at re-challenge or subsequent dose), 19 pts (86%) experienced Grade 2, and 3 pts experienced Grade 3 reaction. Conclusion: Fifty percent of pts with a Grade 2 reaction to pegaspargase were able to tolerate and achieve adequate SAA when re-challenged with premedication. For those who did react with or after re-challenge, reactions were not more severe. The re-challenge approach limits premedication exposure only to a minority of pts with a history of prior reaction and substantially decreases the number of pts needing to switch to Erwinia asparaginase, which can be challenging to deliver due to administration schedule and drug shortage. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.

Management of hypersensitivity reactions to enzyme replacement therapy in children with lysosomal storage diseases

BackgroundIntravenous recombinant enzyme replacement therapy (ERT) is currently available for 8 lysosomal diseases. Hypersensitivity reactions (HSRs) may be observed during this long-term treatment. ObjectiveTo evaluate the frequency and clinical treatment features of ERT HSRs and the management of desensitizations in children. MethodsMedical records were reviewed retrospectively for patients who received ERT. Those who had experienced HSRs to ERT were included in the study. The demographic characteristics of the patients, culprit enzyme, signs and symptoms, diagnostic tests, management of the reaction, and the protocol employed for the maintenance of ERT were recorded. ResultsDuring the study period, 54 patients received ERT in our institution. A total of 11 patients (20.4%) experienced HSR to ERT. All reactions were of immediate type. The most common symptoms were cutaneous manifestations. A total of 9 patients experienced urticaria, and 2 had anaphylaxis as initial reaction. Patients who had isolated cutaneous symptoms continued their treatments with antihistamines, corticosteroid premedication, slower infusion rate or both. Patients who had recurrent urticaria with these modalities or those who had anaphylaxis continued their ERT with desensitization (n = 8). A total of 3 patients required revisions in desensitization protocols because of recurrent anaphylaxis. ConclusionThe reactions that develop during this long-term treatment may be treated by premedication-prolonged infusion, but in some patients, desensitization protocols are necessary for the continuation of therapy. Revisions in desensitization protocols may be required.

Replace Red Man Syndrome With Vancomycin Flushing Reaction.

Imagine this scenario: a 14-year-old Native American boy is being treated with vancomycin for osteomyelitis caused by methicillin-resistant Staphylococcus aureus . During the first infusion, he develops diffuse flushing, which resolves with a slower infusion rate and administration of diphenhydramine. During bedside rounds the next morning, the medical student managing the patient reports that overnight the patient developed red man syndrome. An uncomfortable pause follows as the medical team recognizes the awkwardness of the phrase and as the patient and his family try to understand what message is being conveyed by “red man syndrome”: a term that would seem, erroneously, to invoke race as a key component to its pathophysiology. Providing some historical context is important. In 1959, an article entitled “An anaphylactoid reaction to vancomycin” was published in the Journal of the American Medical Association .1 The pathophysiology of this reaction was hypothesized to involve vancomycin-induced release of histamine from mast cells. Because of this and other untoward effects (eg, oto- and renal toxicity), vancomycin (a name derived from the word vanquish), was not extensively used until the proliferation of methicillin-resistant S aureus occurred in the 1970s and 80s.2 Sometime during this …

Effects of 1% lidocaine instillation on overactive bladder induced by bladder outlet obstruction in rats

Lidocaine is a common local anesthetic and antiarrhythmic drug that acts via the local anesthetic effect of blocking voltage-gated sodium channels in peripheral neurons. To evaluate lidocaine as a therapeutic agent, we investigated optimal concentrations and effects of intravesical lidocaine instillation in a bladder outlet obstruction (BOO)-induced rat model of overactive bladder (OAB). To determine the therapeutic dosage of lidocaine, 16 female Sprague-Dawley (SD) rats (mean weight = 200 ± 20 g) were divided into four treatment groups: those receiving saline, 0.5% lidocaine, 1% lidocaine, and 2% lidocaine (n = 4 per group). Twenty-four additional SD rats were divided into two groups to investigate the effect of 1% lidocaine treatment in rats with BOO and normal rats (n = 12 per group). Cystometry was performed by infusing physiological saline and lidocaine into the bladder at a slow infusion rate (0.04 mL/min). Cystometric parameters were analyzed using PowerLab®. The expression of c-Fos, a protein expressed by C-fibers in the spinal cord (L6), was investigated via western blotting. Among the test lidocaine doses, only 1% lidocaine increased the intercontraction interval (ICI) (control mean = 500.56 ± 24.4 s; treatment mean = 641.0 ± 49.3 s; p < .01) without changes in threshold pressure and basal pressure. In the BOO-induced OAB group, the ICI increased significantly after instillation of 1% lidocaine (control mean = 135.8 ± 12.87 s; OAB-group mean = 274.2 ± 33.21 s; p < .01). Detrusor overactivity and non-voiding contraction were observed in the control group but not in rats with BOO after lidocaine instillation. The expression of c-Fos in C-fibers in the spinal cord (L6) decreased significantly after 1% lidocaine treatment in rats with BOO. Intravesical instillation of 1% lidocaine improves cystometric parameters without deterioration of contractility by blocking excessive C-fiber activity in the rat model of BOO-induced OAB. Therefore, instillation of 1% lidocaine has minimal effects on normal nerves while blocking nerves that contribute to OAB. Our findings suggest that intravesical instillation of 1% lidocaine is a useful treatment for OAB.

Clinical Practice Experience with HyQvia in Adults Using Alternative Dosing Regimens and Pediatric Patients: A Retrospective Study.

IntroductionHyQvia (Immune Globulin Infusion 10% [Human] with Recombinant Human Hyaluronidase) was developed to combine the advantages of intravenous and subcutaneous immune globulin (SCIG), allowing administration of larger volumes at a single subcutaneous site with less frequent dosing when compared to other SCIG products. Current US prescribing guidelines for HyQvia are limited to adults and do not encompass the flexibility required to achieve success in all patients with primary immunodeficiency (PID).MethodsThis retrospective study was designed to evaluate the clinical experience of treating patients with PID with HyQvia regimens outside of package insert recommendations as well as in pediatric patients. Data were abstracted from 38 patient records (317 HyQvia infusions), including five patients less than 16 years of age, from seven US immunology clinics.ResultsAmong 37 patients receiving HyQvia regimens differing from prescribing guidelines, the most notable variations included shorter ramp-up periods, use of two rather than one infusion site, and slower than maximal infusion rates to mitigate local adverse events (AEs). The medication volume infused for single site doses ranged from 75 to 200 mL and doses split between two sites ranged from 100 to 750 mL. The most common type of regimen variation was a condensed ramp-up phase (shorter schedule, higher doses), and 96% (24/25) of patients managed in this way completed ramp-up. The most common ramp-up schedule was three infusions (one at 25–45%, another at 50–75%, and the final at 100% of target dose) spread over 2–4 weeks.ConclusionsA shorter ramp-up schedule did not appear to increase the number of AEs compared to standard ramp-up schedules. For patients with AEs, slower infusion rates and the use of two sites may improve medication tolerability. Four of five pediatric patients reported no AEs, and only one discontinued, stating a fear of needles. HyQvia may be tailored to adults requiring alternative rates, ramp-up, and/or dosing regimens and may be especially well-suited to children.Electronic supplementary materialThe online version of this article (10.1007/s12325-020-01264-7) contains supplementary material, which is available to authorized users.

Rapid Infusion with CT-P10 in Patients with Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukaemia: Interim Six Month Follow-up from a European Non-Interventional Post-Authorisation Safety Study

Rapid Infusion with CT-P10 in Patients with Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukaemia: Interim Six Month Follow-up from a European Non-Interventional Post-Authorisation Safety Study

Temporal effects of ruminal infusion of propionic acid on hepatic metabolism in cows in the postpartum period

A faster rate of infusion of propionic acid into the rumen of cows in the postpartum period increased meal size compared with a slower rate of infusion in a previous experiment. Because propionate is anaplerotic and stimulates oxidation of acetyl coenzyme A (CoA) in the liver, and hepatic oxidation has been linked to satiety, this result was opposite to our expected response. We then hypothesized that the faster rate of infusion might have saturated the pathway for propionate metabolism in hepatocytes resulting in lower first-pass extraction by the liver. Because we were measuring feeding behavior, we could not sample blood and liver tissue over time in that experiment. Therefore, to determine the temporal effects of propionic acid (PA) infusion on hepatic metabolism and plasma metabolites over the time course of a meal, we infused 1.25 mol of PA (2.5 L of 0.5M PA) over 5 min (FST) or 15 min (SLW) into the rumen. We evaluated response to PA infusions both before feeding, when ruminal PA production by rumen microbes is lower and hepatic acetyl CoA concentration is greater, and 4 h after feeding, when PA production is greater and hepatic acetyl CoA concentration is lower. Blood and liver samples were collected before, and after 5, 15, and 30 min of infusion. Contrary to our hypothesis, the rate of PA infusion into the rumen did not affect plasma propionate concentration, indicating the FST effects on feeding behavior were not because of a limitation on propionate uptake by the liver. However, FST increased plasma glucose and insulin concentrations faster than SLW, resulting in a reduction in plasma nonesterified fatty acid concentration during the time frame of meals. Decreased plasma nonesterified fatty acid concentration during infusion likely decreased the supply of acetyl CoA for oxidation in the liver. The FST treatment also increased fumarate concentration at 5 min after the initiation of infusion but did not affect oxaloacetate concentration compared with SLW, consistent with a limitation to propionate metabolism at that reaction. A metabolic bottleneck at the malate dehydrogenase reaction for FST compared with SLW would further contribute to a reduction in hepatic oxidation within the time frame of a meal, allowing greater meal size, consistent with the hepatic oxidation theory and our previous results.

Factors associated with headache in intravenous immunoglobulin treatment for neurological diseases.

To identify possible risk factors influencing the incidence of intravenous immunoglobulin (IVIg) treatment-related cephalalgia in neurological diseases. Retrospective chart review of neurological patients receiving IVIg treatment between July 13, 2017, and August 14, 2017. Patients with MS receiving natalizumab in the same setting were observed as a reference group. Patients with headache after IVIg infusion (n=22 infusions) showed a reduced heart rate (by 6.0±8.5 beats per minute [bpm]), but no significant difference in blood pressure. Patients without headache after IVIg infusion (n=69 infusions) showed a higher systolic blood pressure increase and a stronger reduction in the heart rate (by 5.7±8.6bpm), compared to patients with headache after IVIg infusion. The infusion rate was significantly slower and age significantly lower in patients developing headache after IVIg infusion. Body temperature was unchanged in both groups. Binary logistic regression analysis revealed that blood pressure at baseline and age significantly influence the occurrence of cephalalgia. In reference, patients receiving natalizumab (ie, shorter infusions/smaller infusion volume), systolic blood pressure, and heart rate decreased, while body temperature increased. Here, one patient developed headache. Intravenous immunoglobulin-associated headache is not associated with an increased blood pressure after infusion but with a reduced heart rate, a slower infusion rate, female sex and seems to be influenced by baseline systolic blood pressure and age. A reaction to immunoglobulin aggregates, stabilizers, or vasoactive mediators are possible explanations. The absence of an association with body temperature does not suggest a systemic immune response as a cause for headache.