Escalation Group Research Articles

Continuous heart monitoring to evaluate treatment effects in pulmonary hypertension

Abstract Background The treatment of pulmonary hypertension (PH) has improved rapidly in recent years, and there is increasing evidence to support the role of early intervention. However, studies demonstrate that timely intervention is often still lagging which affects clinical outcomes in patients with PH. Purpose To assess treatment effects after escalation of specific PH treatments using continuous heart monitoring via a Reveal LINQ loop recorder. Methods The patients change in heart rate variability (HRV), heart rate (HR), and physical activity were assessed before and after treatment escalation. Treatment escalation was defined as an additional PAH drug, pulmonary endarterectomy (PEA), percutaneous balloon angioplasty (PBA), or bilateral lung transplantation (BLTX). Results In this prospective study, 41 patients (27 with PAH and 14 with chronic thromboembolic pulmonary hypertension) were enrolled. Among them, 15 patients (36.6%) underwent PH treatment escalation. Prior to escalation, patients were monitored for a median of 100 (range: 68–100) days and after therapy escalation for a median duration of 165 (range: 89–308) days. In the escalation group, a significant increase in HRV (Figure), physical activity indexed by daytime HR was observed, while a significant decrease was seen in nighttime HR assessed at baseline and after treatment escalation. These changes were found both in the PAH and CTEPH group. In parallel a significant improvement in WHO functional class, 6-minute walking distance, and N-terminal pro-b-type natriuretic peptide (NT-proBNP) was observed. Conclusions This is the first study to demonstrate a direct association between specific PH therapies and changes in HRV, HR nighttime and physical activity in patients with PAH and CTEPH. Continuous monitoring allows for an early intervention with supplementary treatment for PH. This is especially relevant considering the increasing availability of wearables that allow for a convenient measurement of relevant prognostic parameters in PH.

Single centre observational study evaluating the impact of introducing High Flow Nasal Cannula outside of Paediatric Critical Care Unit.

To evaluate the impact of High Flow Nasal Cannula (HFNC) introduction outside of Paediatric Critical Care Units (PCCU), on PCCU admissions and intubation rates. Secondarily, to identify escalation predictors. Retrospective observational study with matched PCCU admissions and intubation rates, 2-years before (Group 1) and 2-years after (Group 2) HFNC introduction outside of PCCU. Within Group 2, we compared those admitted to PCCU (escalation) and those who did not (non-escalation). Observations, change in observations and time to starting HFNC were analysed. Pre- and post-introduction comparison: Of 980 admissions in Group 1, 55 were admitted to PCCU, whereas of 1209 admission in Group 2, there were 85 admissions, P = 0.188. Group 1 had 25 intubations compared to 23 in Group 2, P = 0.309. Over twice as many children had some form of respiratory support in Group 2. Post-introduction: 104 children commenced HFNC, 72% for bronchiolitis. Median age was 4 months in the non-escalation group and 6.5 months in the escalation group, P = 0.663. Thirty-eight children escalated to PCCU: 33 required CPAP/BiPAP, 4 were intubated with 1 remaining on HFNC. Comparisons of age, gender, comorbidities, observations, change in observations and time to starting HFNC showed no significant escalation predictors. This study identified no statistically significant predictors of escalation. There was an observed increase in PCCU admissions with decreased intubations. The resource implications of this therapy are significant and further studies should examine cost effectiveness of HFNC use outside of PCCU.

Continuous heart monitoring to evaluate treatment effects in pulmonary hypertension

BackgroundThe treatment of pulmonary hypertension (PH) has improved rapidly in recent decades. There is increasing evidence to support the role of early intervention and treatment in affecting clinical outcomes in...

Rates, Predictors, and Outcomes of Ustekinumab Dose Escalation in Inflammatory Bowel Disease.

Ustekinumab (UST) is effective for the induction and maintenance of remission in inflammatory bowel disease (IBD). However, a significant proportion of patients will require UST dose escalation. We sought to determine the rates, predictors, and outcomes of UST dose escalation in patients with IBD. This was a multicenter, retrospective study of all patients with IBD who received UST from January 1, 2014 to March 1, 2022. Primary outcomes were the rates and predictors of UST dose escalation. Secondary outcomes included steroid-free clinical remission, endoscopic healing, and normalization of serum c-reactive protein in patients who underwent UST dose escalation. A total of 198 patients were included (58% females and 76.7% with Crohn's disease). UST dose was escalated by 55.5% (n = 110). Mean baseline albumin was lower in the UST dose escalation group at 3.86 ± 0.47 versus 4.03 ± 0.45g/dL (P = 0.044). The mean hemoglobin was lower in the UST dose escalation group at 12.1 ± 1.83 versus 12.7 ± 1.42 (P = 0.049). On multivariate analysis, male sex alone was associated with the need for dose escalation (odds ratio: 4.08, 95% CI: 1.20 - 13.90; P = 0.025). In the UST dose escalation group, 66.1% achieved steroid-free clinical remission, 55.8% had normalization of c-reactive protein, and 35.8% achieved endoscopic healing. UST dose escalation was needed in more than half of patients with IBD in this real-world cohort. UST dose escalation resulted in clinical remission in more than half of the cohort and endoscopic healing in one-third of patients.

Rituximab, gemcitabine and oxaliplatin in relapsed or refractory indolent and mantle cell lymphoma: results of a multicenter phase I/II-study of the German Low Grade Lymphoma Study Group

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005.

Sequential treatment escalation improves survival in patients with Waldenstrom macroglobulinemia.

Waldenstrom macroglobulinemia (WM) is a type of incurable, indolent B-cell lymphoma that is prone to relapse. Over time, treatment strategies have progressed from cytotoxic drugs to rituximab (R)- or bortezomib (V)-based regimens, and have now entered into an era of Bruton tyrosine kinase inhibitor (BTKi)-based regimens. However, the optimal treatment for the relapsed patients is still unclear. Herein, we analyzed the outcomes of the first- and second-line therapies in 377 patients with WM to illustrate the optimal choices for second-line therapy. After a median follow-up of 45.4 months, 89 patients received second-line therapy, and 53 patients were evaluated for response. The major response rates (MRR) of first- and second-line treatment were 65.1% and 67.9% (P = 0.678). The median progression-free survival (PFS) for the second-line therapy (PFS2) was shorter than that for the first-line therapy (PFS1) (56.3 vs 40.7 months, P = 0.03). However, PFS2 in targeted drugs group (R-/V-/BTKi-based regimens) was comparable to PFS1 (60.7 months vs 44.7 months, respectively, P = 0.21). Regarding second-line therapy, patients who underwent sequential treatment escalation-such as transitioning from cytotoxic drugs to R-/V-/BTKi-based regimens or from R-/V-based to BTKi-based regimens (escalation group) -had higher MRR (80.6% vs 47.1%, respectively, P = 0.023) and longer PFS2 (50.4 vs 23.5 months, respectively, P < 0.001) compared to the non-escalation group. Patients in the escalation group also had longer post-relapse overall survival compared with the non-escalation group (median, 50.4 vs 23.5 months, respectively, P = 0.039). Our findings indicate that sequential treatment escalation may improve the survival of patients with WM.

Alrizomadlin (APG-115) Alone or Combined with Azacitidine (AZA) in Patients (pts) with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) or Relapsed or Progressive Higher-Risk Myelodysplastic Syndrome (HR-MDS): Phase 1b Trial Results

*Drs. Yifan Zhai and Jianxiang Wang are co-corresponding authors. Background Pts with R/R AML and HR-MDS failing hypomethylating agents have limited therapeutic options and relatively dismal outcomes with available therapies. Investigational alrizomadlin is a novel, orally active, potent, small-molecule selective inhibitor that destabilizes the p53-MDM2 complex and activates p53-mediated apoptosis in tumor cells and has shown apoptotic activity in AML and MDS xenograft models, alone and combined with AZA. Here, we present safety and efficacy results of this therapy in these pts. Methods This open-label dose escalation and expansion trial included adults with R/R AML or relapsed/progressed HR-MDS (IPSS-R ≥ 4.5). MTD and RP2D of alrizomadlin ± AZA were determined by dose escalation. Alrizomadlin (100/150/200/250 mg) was administered orally on Days (D) 1-7 in 28-day cycles. In the combination dose escalation group, alrizomadlin (100/150/200 mg) + AZA (75 mg/m 2) was administered orally once daily on D 1-7 in 28-day cycles and at the combination RP2D during dose expansion. Responses were assessed per revised International Working Group (IWG) Response Criteria 2003, ELN 2017 classifications for AML, and IWG 2006 for MDS. Extensive pharmacokinetic (PK) analyses were performed. Results As of June 1, 2023, 29 pts were enrolled in China. In the monotherapy group, 21 pts (median [range] age, 65 [32-76] years; 76.2%, R/R AML) had a median (range) of 2 (1-10) prior lines of therapy. In the combination group, 8 pts (median [range] age of 69.5 [20-76] years; 50%, R/R AML) had a median (range) of 2 (1-4) prior lines of therapy. In both groups, common any-grade treatment-related adverse events (TRAEs; ≥ 20%) were hematologic- and gastrointestinal-related toxicities, hypokalemia, and dizziness, and most grade ≥ 3 TRAEs were hematologic toxicities. No grade ≥ 3 gastrointestinal toxicities were reported (Figure 1). One DLT, a pulmonary embolism (PE), was reported among 6 evaluable patients at the alrizomadlin 100 mg + AZA dose level: a 59-year-old pt with MDS had a prior COVID-19 infection and abnormal coagulation function before (and during) study treatment. The study investigator attributed the PE to the pt's COVID-19 infection, age, primary disease, and long-term bed rest. One pt in each arm discontinued treatment because of AEs. In pts with AML, the overall response rate (ORR) was defined as complete remission (CR) + CR with incomplete hematologic recovery (CRi) + partial response (PR) + morphologic leukemia-free state (MLFS). In pts with MDS, ORR was defined as CR + PR + marrow CR (mCR). In the monotherapy group, the ORR and CR/CRi rates among pts with R/R AML were 25% (4/16) and 18.75% (3/16), respectively. Three of 6 pts with MDS that progressed to R/R AML experienced responses, including 2 CRis and 1 MLFS. One of 10 pts with R/R AML treated with venetoclax + HMA experienced a CRi. In the monotherapy cohort, 4 pts with MDS refractory to HMAs were evaluated, of whom 2 experienced an mCR. The monotherapy RP2D was determined as 200 mg. In the combination group, 6 pts had an efficacy evaluation at least once. Among these pts, 3 of 3 with MDS experienced an mCR and 1 of 3 with R/R AML, MLFS. Among 4 pts with prior venetoclax + HMA treatment, 2 with MDS experienced an mCR and 2 with R/R AML showed a half marrow blast reduction at the end of C1 (Table 1). No PK drug-drug interaction between alrizomadlin and AZA was observed. Conclusions Alrizomadlin alone or combined with AZA demonstrated a manageable safety profile and preliminary efficacy in pts with R/R AML and HMA-refractory MDS. An antileukemic effect was observed in both monotherapy and combination settings, including a few pts whose disease failed on prior venetoclax treatment. Evaluation of the alrizomadlin + AZA cohort is ongoing. Internal study (CT.gov) identifiers: APG-115-AC101 (NCT04275518).

Nurse management of noradrenaline infusions in intensive care units: An observational study

BackgroundIntensive care nurse management of noradrenaline (norepinephrine) infusions is a common and essential clinical competency for patient haemodynamic support. Nurses titrate and wean noradrenaline infusions to a target blood pressure in a dynamic, high-risk, and unpredictable environment. Titration and weaning are complex interventions, and blood pressure goals are often variable. ObjectivesThe aim was to examine how nurses used blood pressure targets when escalating, weaning, and titrating noradrenaline in intensive care patients admitted for haemodynamic management and explore patient blood pressure responses to changes in noradrenaline doses. MethodsIn this naturalistic observational study, noradrenaline dose changes were classified as escalation, weaning, and titration changes and analysed to explore nursing practice. The study was undertaken in two adult medical/surgical intensive care units in Melbourne, Australia. Participants included intensive care nurses and patients who received noradrenaline infusions for haemodynamic support. ResultsObservations of 14 nurse–patient dyads provided 25 h of blood pressure and noradrenaline dose data. Patient participants received weight-adjusted maximum noradrenaline doses of between 0.06 mcg/kg/min and 0.87 mcg/kg/minute, with those in the escalation group receiving dose increases of up to 5 mcg to achieve blood pressure goals. During weaning, patients maintained or increased their blood pressure as noradrenaline doses were decreased. Nurses consistently maintained blood pressures at higher than target goals, and despite constant fluctuations, they only documented blood pressure readings hourly. ConclusionsIntensive care nurses managed noradrenaline to achieve mean arterial pressure targets that were variable and not evidence based. The disconnection between observed blood pressure fluctuations and nurse documentation of patient blood pressures was reflected in titration practices. Discrepancies between documented and actual blood pressures raised issues about data used by nurses and doctors to inform clinical practice on noradrenaline management.

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA

Temporal order of sexual offending is risk-relevant for individuals with child sexual exploitation materials offences

The current study examined the extent to which the temporal order of sexual offending may be risk-relevant for men with Child Sexual Exploitation Material (CSEM; also referred to as child pornography) offences. We categorized 85 men who had committed two distinct sexual offences (CSEM or contact sexual offence) into three groups: (1) 47% (n = 40) followed a stable pattern, that is, men with CSEM offences who then committed a new CSEM offence; (2) 41% (n = 35) followed a de-escalation pattern, that is, men with contact sexual offences who then committed a CSEM offence; (3) and 12% (n = 10) followed an escalation pattern, that is, men with CSEM offences who then committed a contact sexual offence. Compared to the other groups, the stable group had more sexual interest in children, the de-escalation group had a younger age at first police involvement and more prior offending, and the escalation group had more substance use problems. We then examined recidivism (any new offence after the second sexual offence) and found that the escalation group had the highest 5-year and 7-year reoffending rates (start of follow-up: opportunity after the second sexual offence) for any crime, any non-sexual violence, any violence (including contact sexual offences), and any contact sexual recidivism. The de-escalation and stable groups had the highest CSEM recidivism rates. The current study suggests that ordering of offending within men adjudicated for CSEM offences is risk-relevant and that those who fit the escalation pattern may be at higher risk to reoffend.

Dutch Gastrointestinal Stromal Tumor (GIST) Registry Data Comparing Sunitinib with Imatinib Dose Escalation in Second-Line Advanced Non-KIT Exon 9 Mutated GIST Patients.

The prognosis of patients with advanced gastrointestinal stromal tumor (GIST) has improved greatly after theintroduction of imatinib. However, primary or secondary resistance to imatinib occurs in the majority of patients. Sunitinib is the standard second line treatment in exon-9 mutated GIST. We compared the clinical outcomes of sunitinib with imatinib dose escalation in patients with progressive advanced non-KIT exon 9 mutated GIST after failure of first line imatinib. A retrospective study was performed, retrieving data from a real-life database (Dutch GIST Registry) including patients with GIST treated with sunitinib or imatinib dose escalation after failure on first line imatinib 400 mg daily. Primary outcome measures were progression free survival (PFS) and overall survival (OS). In total, 110 patients were included, 72 (65.5%) patients were treated with sunitinib (group A) and 38 (34.5%) received an imatinib dose escalation (group B). Important prognostic features at baseline, such as tumor size, stage at diagnosis, mitotic count and localization were equally distributed in both groups. No significant difference (p = 0.88) between median PFS in group A [8.7 months (95% CI 5.6-11.3)] and group B [5.6 months, (95% CI 2.6-8.7)] was observed. Moreover, the OS was similar between group A and group B; 63.2 months and 63.4 months, respectively. This study represents a proper sample size cohort containing detailed data on mutational status of patients with advanced GIST. We illustrated that imatinib dose escalation could serve as a good alternative for sunitinib as second-line treatment in patients with a non-KIT exon 9 mutation.

Safety, efficacy, pharmacokinetics of uliledlimab alone or combined with toripalimab in advanced solid tumor: Initial results of a phase I/II study.

e21123 Background: Upregulation of CD73 results in the adenosine overproduction, which suppresses immune responses in tumoral microenvironment. Uliledlimab (ULI), a differentiated anti-CD73 antibody, inhibits adenosine generation in a non-competitive manner and suppresses tumor growth when combined with a PD-(L)1 inhibitor. Methods: The dose-escalation and dose expansion phase I/II study (NCT04322006) was designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of ULI alone, or combined with toripalimab (TOR) in patients with advanced solid tumor. ULI was administered iv. at 2, 5,10 mg/kg weekly (QW) or at 15, 20, 30 mg/kg every 3 weeks (Q3W) alone, or combined with TOR (240 mg, iv, Q3W) in dose escalation. Preliminary efficacy of ULI (20 mg/kg Q3W) + TOR (240 mg Q3W) was examined in non-small cell lung cancer (NSCLC) in dose expansion cohorts. Serum concentration of ULI and soluble CD73, CD73 receptor occupancy (RO) in circulating CD19+ B cells were detected. Tumor response was assessed by RECIST1.1/iRECIST. Results: As of 12/5/2021, a total of 92 patients were enrolled: 12 in dose escalation of ULI alone, 9 in ULI+TOR dose escalation group, and 71 in ULI+TOR dose expansion cohorts. ULI was well-tolerated with no DLT observed in dose escalation. Most of treatment-related adverse event (TRAE) were grade 1-2 with grade 3-4 TRAE occurring in 2 patients with decreased lymphocyte count and 1 with transient QT prolongation in ULI monotherapy group, and 2 patients each with hypotension and diarrhea as most reported events in ULI+TOR group. Most common TRAE were grade 1-2 chills (47.8%), vomiting (46.7%), pyrexia (40.2%), diarrhea (32.6%), nausea (19.6%), pruritus (14.1%), rash (13%) that occurred after the first dose of ULI and resolved in subsequent infusions, which can be significantly reduced by steroid-based premedication. The PK of ULI was linear at doses ≥ 5 mg/kg and modelling indicated a mean derived effective t1/2 of ̃13.2 days. Soluble CD73 was undetectable and complete RO was maintained after the first dose at ≥ 15 mg/kg Q3W at Ctrough throughout the dosing interval. As of 12/13/2021, among 48 efficacy-evaluable NSCLC patients in dose expansion cohorts, 6 partial responses (PR) (ORR 12.5%, 95%CI: 4.7%-25.2%) and 21 stable diseases (DCR 56.4%, 95%CI, 41.2%-70.5%) were observed. PRs were observed in 3 out of 8 systematic treatment-naïve patients, and 3 out of 39 patients with relapse/refractory disease to previous systematic treatment including 2 patients received no prior PD-(L)1 inhibitor treatment and 1 patient failed pembrolizumab. Conclusions: ULI was safe and tolerated up to 30 mg/kg Q3W. Linear PK observed at doses ≥ 5 mg/kg with t1/2 of 13.2 days. Full saturation of circulating and cell-bound CD73 was maintained at doses ≥ 15 mg/kg Q3W. ULI combined with TOR exhibited evidence of anti-tumor activity in NSCLC patients. Clinical trial information: NCT04322006.

Allopurinol Initiation and All-Cause Mortality Among Patients With Gout and Concurrent Chronic Kidney Disease : A Population-Based Cohort Study.

Two recent randomized clinical trials of escalating doses of allopurinol for the progression of chronic kidney disease (CKD) reported no benefits but potentially increased risk for death. Whether the risk could occur in patients with gout and concurrent CKD remains unknown. To examine the relation of allopurinol initiation, allopurinol dose escalation, and achieving target serum urate (SU) level after allopurinol initiation to all-cause mortality in patients with both gout and CKD. Cohort study. The Health Improvement Network U.K. primary care database (2000 to 2019). Patients aged 40 years or older who had gout and concurrent moderate-to-severe CKD. The association between allopurinol initiation and all-cause mortality over 5-year follow-up in propensity score (PS)-matched cohorts was examined. Analysis of hypothetical trials were emulated: achieving target SU level (<0.36 mmol/L) versus not achieving target SU level and dose escalation versus no dose escalation for mortality over 5-year follow-up in allopurinol initiators. Mortality was 4.9 and 5.8 per 100 person-years in 5277 allopurinol initiators and 5277 PS-matched noninitiators, respectively (hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.93]). In the target trial emulation analysis, the HR of mortality for the achieving target SU level group compared with the not achieving target SU level group was 0.87 (CI, 0.75 to 1.01); the HR of mortality for allopurinol in the dose escalation group versus the no dose escalation group was 0.88 (CI, 0.73 to 1.07). Residual confounding cannot be ruled out. In this population-based data, neither allopurinol initiation, nor achieving target SU level with allopurinol, nor allopurinol dose escalation was associated with increased mortality in patients with gout and concurrent CKD. Project Program of National Clinical Research Center for Geriatric Disorders.

An observational longitudinal study of the use of ROX index to predict treatment failure in patients receiving continuous positive airway pressure for COVID-19.

An observational longitudinal study of the use of ROX index to predict treatment failure in patients receiving continuous positive airway pressure for COVID-19.

De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis

Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detailed mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular traps (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy in cecum ligation and puncture (CLP) models. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. In CLP models, de-escalation therapy resulted in an increased serum MPO-DNA level during the early stage and decreased MPO-DNA level during late stage, which exerted the reverse effects in escalation therapy. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAse I during the early stage of sepsis (p < 0.01). Histopathological analysis showed decreased injury in lung, liver, and intestine in de-escalation therapy compared with escalation therapy (p < 0.01). De-escalation therapy results in the highest 6-day survival rate compared with the control group (p < 0.01), however, no significant difference was found between de-escalation and escalation group (p = 0.051). The in vitro study showed that the imipenem could promote, while the ceftriaxone could inhibit the formation of NETs in PMA-activated PMNs through a ROS-dependent manner. We firstly demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage, and inhibiting NETs formation in the late stage of sepsis.

Patterns of drug therapy, glycemic control, and predictors of escalation- non-escalation of treatment among diabetes outpatients at a tertiary care center.

The study was conducted to assess patterns of prescribed drug therapy and clinical predictors of need for therapy escalation in outpatients with diabetes mellitus (DM). This was a prospective cohort study, conducted at an apex tertiary care teaching hospital in central India for a period of 18months. The demographic, clinical, and treatment details on the baseline and follow up visits were collected from the patients' prescription charts. Glycemic control, adherence, pill burdens along with pattern of antidiabetic therapy escalation, and deescalations were analyzed. A total of 1,711 prescriptions of 925 patients of diabetes with a mean age of 53.81±10.42years and duration of disease of 9.15±6.3years were analyzed. Approximately half of the patients (n=450) came for≥1 follow up visits. Hypertension (59.35%) was the most common comorbidity followed by dyslipidemia and hypothyroidism. The mean total daily drugs and pills per prescription were 4.03±1.71 and 4.17±1.38, respectively. Metformin (30.42%) followed by sulphonylureas (SUs) (21.39%) constituted majority of the AHA's and dual and triple drug therapy regimens were most commonly prescribed. There were improvements in HbA1c, fasting/postprandial/random blood sugar (FBS/PPBS/RBS) as well as adherence to medication, diet, and exercise in the follow up visits. Among patients with follow ups, therapy escalations were found in 31.11% patients, among whom dose was increased in 12.44% and drug was added in 17.28%. Apart from Hb1Ac, FBS, and PPBS levels (p<0.001), characteristics such as age, BMI, duration of diagnosed diabetes, presence of hypertension and dyslipidemia, and daily pill burdens were found to be significantly higher in the therapy escalation group (p<0.05). Inadequate medication adherence increased the relative risk (RR) of therapy escalation by almost two times. Disease and therapy patterns are reflective of diabetes care as expected at a tertiary care center. Higher BMI, age, pill burden, duration of diabetes, presence of comorbidities, and poor medication adherence may be the predictors of therapy escalation independent of glycemic control and such patients should be more closely monitored.

Comparison of two dose escalation strategies of methotrexate in active rheumatoid arthritis: a multicentre, parallel group, randomised controlled trial

ObjectivesThere are no head-to-head trials of different dose escalation strategies of methotrexate (MTX) in RA. We compared the efficacy, safety and tolerability of ‘usual’ (5 mg every 4 weeks) versus...

Escalation of liPid-lOwering therapy in patientS wiTh vascular disease receiving HIGH-intensity statins: the retrospective POST-HIGH study

In this retrospective study, we investigated whether lipid-lowering therapy (LLT) escalation has clinical benefits in patients with atherosclerotic cardiovascular disease (ASCVD) and low-density lipoprotein cholesterol (LDL-C) levels of 55–99 mg/dL (1.4–2.6 mmol/L), post high-intensity. Out of 6317 Korean patients screened in 2005–2018, 1159 individuals with ASCVD and LDL-C levels of 55–99 mg/dL after statin use equivalent to 40 mg atorvastatin were included. After 1:2 propensity score matching, 492 patients (164 with LLT escalation, 328 controls without LLT escalation) were finally analysed. Primary outcome variables were major adverse cardiovascular and cerebrovascular events (MACCE) and all-cause death. At median follow-up (1.93 years), the escalation group had a lower MACCE rate (1.72 vs. 3.38 events/100 person-years; hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.14–0.83; p = 0.018) than the control group. The incidence of all-cause death (0.86 vs. 1.02 events/100 person-years; HR 0.58, 95% CI 0.15–2.19; p = 0.42) and each MACCE component did not differ between groups. Kaplan–Meier curves exhibited lower risk of MACCE in the escalation group (HR 0.36, 95% CI 0.12–0.97; p = 0.040) but a difference not statistically significant in all-cause death (HR 0.30, 95% CI 0.04–2.48; p = 0.26). LLT escalation was associated with reduced cardiovascular risk, supporting more aggressive LLT in this population.

Utilisation of RAM cannula for non-invasive respiratory support for infants in the cardiac ICU.

Children with CHD carry an additional burden of pulmonary insufficiency, often necessitating prolonged ventilatory support, especially in the peri-operative phase. There has been an increase in the utilisation of non-invasive ventilatory support for these children. The objective of this study was to evaluate the utilisation, safety, and outcomes of RAM cannula as a tool for escalation and de-escalation of respiratory support in paediatric cardiac patients less than one year of age. A single-centre retrospective cohort study of patients supported with RAM cannula. A total of 275 instances of RAM use were included in the study, 81.1% being post-operative. Patients were stratified into escalation and de-escalation cohorts based on the indication of non-invasive ventilation. The success rate of using RAM cannula was 69.5% overall, 66.1% in the escalation group, and 72.8% in the de-escalation group. At baseline, age at cardiac ICU admission >30 days, FiO2 ≤ 40%, PaCO2 ≤ 50 mmHg; and after 12 hours of non-invasive ventilation support respiratory rate ≤ 60/min, PaO2 ≥ 50 mmHg, PaCO2 ≤ 50 mmHg; and absence of worsening on follow-up chest X-ray predicted the success with a sensitivity of 95% in the logistic regression model. Successful support was associated with a significantly shorter unit stay. RAM cannula can be safely used to provide non-invasive support to infants in the cardiac ICU for escalation and de-escalation of respiratory support. Factors associated with success can be used to make decisions about candidacy and appropriate timing of non-invasive ventilation use to maximise effectiveness.

Association between opioid dose escalation and time to death in a comfort measures only population

PurposeOpioids are crucial to the relief of pain and dyspnea experienced by patients dying in the hospital setting; however, there are concerns about the association of opioid dosage with hastened death via opioid-induced respiratory depression, and there is little published evidence regarding the association between opioid dose escalation and time to death in the inpatient comfort measures only (CMO) population.MethodsThe medical records of adult patients admitted to 2 hospitals who had an active CMO order at the time of death and received opioid dose escalations after CMO pronouncement were assessed in a retrospective cohort study. Patients were categorized into higher and lower opioid dose escalation groups according to an institutional palliative care symptom guide. A Cox proportional hazards model was constructed to test the associations between dose escalation group, patient sex, opioid naivety, palliative care consultation, and opioid dosage after CMO pronouncement (independent variables) and time to death (dependent variable).ResultsIn the 71-patient cohort, 39 patients (54.9%) were male and 32 (45.1%) were female. The mean (SD) age of patients was 67.2 (16.6) years. Higher dose escalation (n = 46, 64.8%) was associated with a nonsignificant decrease in survival time compared to lower dose escalation (n = 25, 35.2%), with a mean difference in time to death of 19.8 hours (hazard ratio [HR], 1.67; 95% confidence interval [CI], 0.94-2.97). Receipt of a palliative care consult (n = 56, 78.9%) during the final hospital visit was associated with increased survival time (mean difference, 20.1 hours; HR, 0.32; 95% CI, 0.16-0.63).ConclusionTime to death in an inpatient CMO population was not significantly associated with the degree of opioid dose escalation.