Final Infusion Rate Research Articles

Evaluation of an adaptive, rule-based dosing algorithm to maintain therapeutic anticoagulation during atrial fibrillation ablation

Cerebral thromboembolism during atrial fibrillation (AF) ablation is an infrequent (0.17%) complication in part owing to strict adherence to intraprocedural anticoagulation. Failure to maintain therapeutic anticoagulation can lead to an increase in events, including silent cerebral ischemia. To evaluate a computerized, clinical decision support system (CDSS) to dose intraprocedural anticoagulation and determine if it leads to improved intraprocedural anticoagulation outcomes during AF ablation. The Digital Intern dosing algorithm is an adaptive, rule-based CDSS for heparin dosing. The initial dose is calculated from the patient's weight, baseline activated clotting time (ACT), and outpatient anticoagulant. Subsequent recommendations adapt based on individual patient ACT changes. Outcomes from 50 cases prior to algorithm introduction were compared to 139 cases using the algorithm. Procedures using the dosing algorithm reached goal ACT (over 300 seconds) faster (17.6 ± 11.1 minutes vs 33.3 ± 23.6 minutes pre-algorithm, P < .001). ACTs fell below goal while in the LA (odds ratio 0.20 [0.10-0.39], P < .001) and rose above 400 seconds less frequently (odds ratio 0.21 [0.07-0.59], P=.003). System Usability Scale scores were excellent (96 ± 5, n = 7, score >80.3 excellent). Preprocedure anticoagulant, weight, baseline ACT, age, sex, and renal function were potential predictors of heparin dose to achieve ACT >300 seconds and final infusion rate. A heparin dosing CDSS based on rules and adaptation to individual patient response improved maintenance of therapeutic ACT during AF ablation and was rated highly by nurses for usability.

CTNI-28. FINAL RESULTS OF A PILOT STUDY TO EVALUATE INFUSION RATE ESCALATION TO MAXIMIZE VOLUME OF DISTRIBUTION DURING CONVECTION ENHANCED DELIVERY TO CONTRAST-ENHANCING GLIOBLASTOMA

Abstract BACKGROUND Volume of distribution (Vd) during convection enhanced delivery is impacted by the characteristics of the tissue being treated. For Glioblastoma (GBM), Vd is substantially higher in non-contrast enhancing tumor than in contrast enhancing tumor due to higher infusate efflux in enhancing tumor. We hypothesized that increasing the infusion rate could overcome the infusate efflux rate in enhancing tumor to improve the Vd to volume of infusion (Vi) ratio and provide better tumor coverage. METHODS A single center, IRB-approved pilot study was conducted under an IND (held by MAV) to perform rate escalated delivery of Topotecan with Gadolinium-DTPA to contrast-enhancing recurrent GBM (rGBM). A single Cleveland Multiport Catheter was surgically placed into enhancing tumor and then a 4-hour infusion was performed with real-time MRI visualization. Intra- and inter-patient rate escalation was performed. RESULTS 3 patients with rGBM were enrolled and treated. The initial infusion rate for patient 1 was 5 microliters/minute per microcatheter (4 total) and the final infusion rate for the third patient was 20 microliters/minute per microcatheter. We observed partial backflow at this rate and so did not escalate higher. There was coverage of both enhancing and non-enhancing tumor in all cases, and the Vd/Vi ratio ranged from 0.7 to 1.3. Patients tolerated the treatments well; there were no CTCAE Grade 3 or higher treatment related adverse events. CONCLUSIONS The higher efflux rate associate with contrast-enhancing tumor tissue can be overcome with sufficient infusion rate escalation.

Pharmacy-Led Quality Improvement Project on Pain Control Using Continuous Subcutaneous Infusion of Opioids in an Inpatient Hospice Unit.

The purpose of this quality improvement (QI) project was to improve the overall process of implementing continuous subcutaneous infusion of opioids (CSCIOs) at the West Palm Beach Veterans Affairs Medical Center and characterize their use in the hospice unit. A retrospective chart review from July 2014 to August 2017 was conducted to identify patients who had received CSCIO. Results were analyzed with descriptive statistics.The business philosphy, LEANmethodology "The 5 Whys" was utilized to identify the root causes for delayed infusion timeliness and corrections were implemented by August 2018. Follow-up retrospective time study completed from September 2018 to February 2019. Of the 107 patients identified, 7 were excluded and 100 were reviewed. The mean age was 73 years, 94% male, and 86% Caucasian. A total of 55 veterans received morphine with an average final infusion rate of 2.5 mg/h. A total of 45 Veterans received hydromorphone with a final infusion rate of 1.3 mg/h. The average infusion duration until death was 5 days. Pharmacy verified 94 (94%) orders and nursing verified 55 (55%) orders within 1 hour (gold standard). Sixteen (16%) patients received CSCIO within 1 hour. The 5 Whys identified nursing order verification and pharmacy lack of visual STAT order notification for priority as the potential sources for infusion timeliness improvement. The follow-up time study confirmed improvement in pharmacy delivery time from 29% to 75% on time. Pharmacist-led intervention directed to improve CSCIO processes in an inpatient hospice unit utilizing LEAN QI methodology increased timeliness of pharmacy CSCIO delivery.

Rapid Infusion Daratumumab Is Safe in Patients with AL Amyloidosis

Introduction: Daratumumab (DARA) is an anti-CD38 human monoclonal antibody FDA-approved for the treatment of multiple myeloma (MM) and has demonstrated efficacy in AL amyloidosis. Infusion-related reactions (IRRs) occur in over 50% of patients treated with DARA, most commonly with the first infusion despite premedication with corticosteroids, antipyretics, antihistamines, and post-infusion corticosteroids. If DARA is tolerated without IRRs, the infusion rate can be escalated in standardized increments to a final infusion rate administered over 90 minutes in patients with MM (Barr et al. Leukemia 2018). Rapid infusions of DARA decrease length of infusion visits, potentially improving patient satisfaction and optimizing healthcare resources. Recent studies showed that DARA is safe and highly effective in treating AL amyloidosis (Khouri et al, Br J Haematol 2018), but no information is available regarding the safety of administering rapid infusions of DARA in patients with AL amyloidosis. We hypothesized that patients with AL amyloidosis, especially those with cardiac involvement, may not tolerate a rapid administration of fluids. Thus, a DARA rapid infusion protocol for patients with AL amyloidosis was implemented at our institution in April 2018. We report findings from the protocol implementation. Methods: A retrospective observational study was conducted to review adult patients with AL amyloidosis who received rapid infusions of DARA from April 2018 to October 2018. Data collected included relevant past medical history, vitals, premedications, infusion rates, and management of IRRs. Patients were eligible for rapid DARA after tolerating two prior doses of DARA at standard infusion rates. Rapid DARA was infused at 200 mL/hr for 30 minutes, then increased to 450 mL/hr for 60 minutes. Protocol premedications included acetaminophen, diphenhydramine, famotidine, and dexamethasone. No post-infusion corticosteroids were required. The first two standard and first four rapid DARA infusions were evaluated for each patient. Results: 27 patients with AL amyloidosis were included in the study with 162 doses of rapid DARA evaluated. Baseline characteristics included age (median 72 years old), gender (55.6% male), diastolic heart failure (59.3%), combined systolic and diastolic heart failures (11.1%), chronic obstructive pulmonary disease (7.4%), asthma (7.4%), and chronic kidney disease (25.9%). 62.9% of patients had cardiac AL involvement and 51.9% had renal AL involvement. 11/27 (40.7%) patients had IRRs to the first infusion of DARA (cycle 1, day 1) requiring hypersensitivity medications. All 27 patients progressed to rapid rate DARA after both initial and subsequent rates were tolerated. 22/27 (81.5%) patients initiated the first rapid DARA with the protocol premedications. Premedication usage decreased by the fourth rapid DARA dose with only 23.1% patients receiving diphenhydramine, 57.7% receiving famotidine, and 38.5% receiving dexamethasone (Figure 1). No patients received post-infusion corticosteroids. There were no clinically significant IRRs with the DARA rapid infusion protocol across all patients, regardless of organ involvement. There were 10 cases of CTCAE grade 2-3 hypertension that did not require intervention. No hypersensitivity medications were required for any rapid DARA doses. 11/11 (100%) patients who experienced IRRs requiring hypersensitivity medications during their first or second standard DARA infusions tolerated rapid DARA administration without recurrence of IRRs. Conclusions: Rapid administration of DARA is safe and well-tolerated in patients with AL amyloidosis, regardless of organ involvement. Patients who experienced an IRR with the initial DARA dose were able to safely transition to the rapid infusion protocol without recurrence of IRRs. Furthermore, decreased premedication usage after tolerance of rapid DARA infusion did not increase IRRs, suggesting premedications can be discontinued to mitigate associated toxicities. Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau. Valent:Celgene corporation: Speakers Bureau; Amgen corporation: Speakers Bureau; Takeda pharmaceuticals: Speakers Bureau. OffLabel Disclosure: Daratumumab for the treatment of AL amyloidosis

(386) Analgesia and psychosis: intrathecal ziconotide in a young Hospice patient with spinocerebellar ataxia and painful peripheral neuropathy

We describe a 37-year-old woman with an underlying spinocerebellar ataxia who developed severe, painful peripheral neuropathy in 2006. When she presented to our clinic in April 2013, Hospice was providing her 40 mg IV hydromorphone per hour demand plus 10 mg every 10 minutes. She had failed gabapentin, pregabalin, and amitriptyline before coming under our care. Concerned about opiate inefficacy and hyperalgesia, we aggressively weaned (over one month) the patient completely from her hydromorphone. She was then trialed and implanted with an intrathecal pump infusing ziconotide. Over her 11-day inpatient trial, the patient’s pain was reduced markedly at a final infusion rate of 10.8 mcg/day, and she required no other analgesics. After her implant, she even subsequently went on an international religious mission trip. Twenty-seven days after the implant, however, the patient developed psychosis, and the ziconotide was stopped. Her symptoms resolved completely within one day. As an alternative, intrathecal opiates and local anesthetics were infused through the pump immediately thereafter, and for two months, but they failed. So, we decided to restart the ziconotide using a flexible dosing schedule, slowly increasing her daily dose. We used a basal rate of 0.206 mcg/hr plus a 2100 bolus of 2.001 mcg over one hour. Over the subsequent 4 months, we have made incremental increases and decreases in both her basal and bolus dosing, titrating to a balance of analgesia and mental status stability. Her total daily dose is now 11.437 mcg/day. At this time, her pain is again well controlled, she is not taking any opiates, and she has no neuropsychiatric side effects. We describe a 37-year-old woman with an underlying spinocerebellar ataxia who developed severe, painful peripheral neuropathy in 2006. When she presented to our clinic in April 2013, Hospice was providing her 40 mg IV hydromorphone per hour demand plus 10 mg every 10 minutes. She had failed gabapentin, pregabalin, and amitriptyline before coming under our care. Concerned about opiate inefficacy and hyperalgesia, we aggressively weaned (over one month) the patient completely from her hydromorphone. She was then trialed and implanted with an intrathecal pump infusing ziconotide. Over her 11-day inpatient trial, the patient’s pain was reduced markedly at a final infusion rate of 10.8 mcg/day, and she required no other analgesics. After her implant, she even subsequently went on an international religious mission trip. Twenty-seven days after the implant, however, the patient developed psychosis, and the ziconotide was stopped. Her symptoms resolved completely within one day. As an alternative, intrathecal opiates and local anesthetics were infused through the pump immediately thereafter, and for two months, but they failed. So, we decided to restart the ziconotide using a flexible dosing schedule, slowly increasing her daily dose. We used a basal rate of 0.206 mcg/hr plus a 2100 bolus of 2.001 mcg over one hour. Over the subsequent 4 months, we have made incremental increases and decreases in both her basal and bolus dosing, titrating to a balance of analgesia and mental status stability. Her total daily dose is now 11.437 mcg/day. At this time, her pain is again well controlled, she is not taking any opiates, and she has no neuropsychiatric side effects.

Efficacy of a Nurse-Managed Argatroban Dose-Adjustment Protocol in a University Teaching Hospital

Background Argatroban is a direct thrombin inhibitor used in the treatment of heparin-induced thrombocytopenia (HIT). No study has evaluated the safety and efficacy of a nurse-managed argatroban dosing protocol. Methods We performed a retrospective analysis of 151 total admissions (129 patients) in which argatroban infusions were administered before and after protocol implementation. The preprotocol and postprotocol groups consisted of 69 and 68 admissions, respectively. Patients were eligible for inclusion if they were ≥18 years old and received an argatroban drip for any reason in the 2 years prior to or following protocol implementation. Results There were no statistically significant differences in the incidence of clinically overt bleeding (primary study safety endpoint) between groups. There was no difference between groups in the primary efficacy endpoints, the mean number of partial thromboplastin time (aPTT) assessments per day, and dose adjustments. The mean number of sub- and supratherapeutic aPTTs during treatment was higher in the preprotocol group when utilizing the specified range in the preprotocol group and the protocol's aPTT range (45–90 s); the preprotocol and postprotocol groups had an average of 3.4 and 1.04 subtherapeutic aPTTs, respectively ( P = .008). Similarly, the preprotocol group had an average of 4.98 supratherapeutic aPTTs, while the postprotocol group had 1.84 ( P &lt; .001). There was no difference in duration of argatroban infusion in the preprotocol group compared to the postprotocol group with regard to duration of infusion or final infusion rate. Conclusions This nurse-managed argatroban adjustment protocol provides similar safety and efficacy outcomes and decreased monitoring when pre and post implementation were compared.

Pharmacokinetics of Continuous Infusion Therapy of Factor VIII Concentrates in Hemophilia A Patients with Inhibitors,

Abstract 3320▪▪This icon denotes a clinically relevant abstractContinuous infusion (CI) of factor VIII (FVIII) concentrates is aimed at maintaining a steady hemostatic level of FVIII activity (FVIII:C) in hemophilia A patients during various surgeries. However, there are few reports that mentioned the difference of pharmacokinetics of CI therapy in hemophilia A patients with inhibitors. We investigated the relationship between the FVIII:C levels and the rate of CI, and the difference of clearance (CL) and volume of distribution (Vd) of FVIII in hemophilia A patients with/without inhibitors. 8 severe hemophilia A patients without inhibitors (arthroscopic synovectomy; 4 cases, total knee arthroplasty; 2 cases, total nephrectomy; 1 case, partial hepatectomy; 1 case), 3 patients with low-titer (2.0–2.9 BU) inhibitors and 3 patients with high-titer (6.0–9.0 BU) inhibitors (insertion or removal of a central venous access device), were enrolled in this study between 2005 and 2010. According to the Japanese guideline for hemophilia treatment, we should do CI therapy to keep target level 80–100% for 5–10 days for joint surgery and other major surgeries. An initial bolus infusion (BI) of FVIII concentrates was administered to achieve this level prior to CI. In addition, we have to neutralize the inhibitors by FVIII concentrates in case of the patients with inhibitors. FVIII:C was measured using one-stage clotting assays and FVIII inhibitor assays were performed using the Bethesda method. All therapy was conducted after obtaining fully informed consent. The median FVIII:C level after BI was 120.2% (range: 90–150) in the patients without inhibitors, 72.0% (range: 68–160) with low-titer inhibitors, and 20.0% (range: 9.4–30) with high-titer inhibitors, respectively. The target level of FVIII:C was adjusted to approximately 100%. The initial infusion rate was 3.7 U/kg/hr (range: 2.2–5.0), 8.3 U/kg/hr (range: 8.0–8.5) and 18.5 U/kg/hr (range: 15–22), respectively. After adjustment for the target level, the final infusion rate decreased to 2.6 U/kg/hr (range: 1.5–5.4), 4.7 U/kg/hr (range: 3.0–5.6) and 8.0 U/kg/hr (range: 7.0–9.0), respectively. CL was 2.3 ml/hr/kg (range: 1.5–3.9), 4.0 ml/hr/kg (range: 2.3–5.1) and 9.3 ml/hr/kg (range: 9.0–9.6), respectively. Vd was 0.04 L/kg (range: 0.031–0.047), 0.18 L/kg (range: 0.12–0.29) and 1.54 L/kg (range: 0.95–2.43), respectively. No unexpected safety concerns associated with CI, such as thrombosis, was identified during the study. On CI therapy, we could keep target level of the patients without inhibitors and with low-titer inhibitors easier than those with high-titer inhibitors. One of the reason is that CL and Vd in patients with inhibitors are higher than those in patients without inhibitors. CI with appropriate monitoring of FVIII:C level and concerning CL and Vd forms a safe method for perioperative care in hemophilia A patients with inhibitors. Disclosures:No relevant conflicts of interest to declare.

Achievement of anticoagulation by using a weight-based heparin dosing protocol for obese and nonobese patients.

The need for different heparin dosing protocols for obese and nonobese patients was studied. A chart review was performed for all patients who received heparin over an eight-month period at an acute care hospital. Data collected included age, sex, height, actual body weight (ABW), ideal body weight (IBW), initial activated partial thromboplastin time (aPTT), initial heparin bolus dose, initial heparin i.v. infusion rate, time to initial targeted aPTT, and final infusion rate. Forty patients met criteria for inclusion: 20 obese patients (greater than 30% over IBW) and 20 nonobese patients (less than 20% over IBW). Mean +/- S.D. initial heparin infusion rates for the obese and nonobese groups were 14.44+/-1.29 and 15.04+/-0.42 units/kg/hr, respectively. Times to targeted aPTT for obese and nonobese patients were 25.86+/-12.83 and 25.18+/-14.76 hours, respectively; mean final infusion rates were 12.94+/-2.56 and 12.36+/-2.54 units/kg/hr; and percent changes from initial to final infusion rates were 11.84% and 17.76%. There were no significant differences in initial or final infusion rates or time to targeted aPTT between the two groups. It is appropriate to use ABW in a weight-based heparin dosing protocol for obese patients.

Remifentanil as an analgesic adjunct in local/regional anesthesia and in monitored anesthesia care.

Remifentanil as an analgesic adjunct in local/regional anesthesia and in monitored anesthesia care.

Pharmacokinetics and side effects of milrinone in infants and children after open heart surgery.

We investigated the pharmacokinetics and side effects of milrinone in infants and children (< or = 13 yr) after open heart surgery in this prospective, open-label study. Milrinone binding to cardiopulmonary bypass (CPB) circuitry was also examined in out two groups. Children in the small dose group (n = 11) received two 25-microg/kg boluses with a final infusion rate of 0.5 microg kg(-1) x min(-1); those in the large dose group (n = 8) received a 50-microg/kg bolus and a 25-microg/kg bolus with a final infusion rate of 0.75 microg x kg(-1) x min(-1). Blood samples for milrinone concentration were drawn 30 min after each bolus, at steady state, and after discontinuing the milrinone infusion. Pharmacokinetics were evaluated using traditional and nonlinear mixed effects modeling analysis. Milrinone kinetics best fit a two-compartment model. Steady-state plasma levels in the small and large dose groups were within the adult therapeutic range (113 +/- 39 and 206 +/- 74 ng/mL, respectively). The volumes of distribution (Vbeta) in infants (0.9 L/kg) and children (0.7 L/kg) were not different, but infants had significantly lower milrinone clearance (3.8 vs 5.9 mL x kg(-1) x min(-1)). Thrombocytopenia (defined as platelet count < or = 100,000 mm(-3)) occurred in 58%, and the risk increased significantly with duration of infusion. Tachyarrythmias were noted in two patients. Milrinone did not bind to CPB circuitry. We conclude that milrinone is cleared more rapidly in children than in adults. The major complication was thrombocytopenia. Most pediatric dosing is based on data published for adults. Infants and children have kinetics that differ from adults. We studied the distribution of I.V. milrinone in infants and children after open heart surgery. Milrinone had a larger volume of distribution and a faster clearance in infants and children than in adults, and dosing should be adjusted accordingly.

Initial Clinical Experience with Remifentanil, a New Opioid Metabolized by Esterases

Comment The observations in this interesting study are the first clinical data on remifentanil when it is administered as the analgesic component of an opioid-nitrous oxide-relaxant anesthetic. Remifentanil produced hemodynamic effects similar to fen-tanyl and other potent μ-agonists. However, remifentanil may possess a larger margin of safety than other opioid analgesics in terms of rapid recovery, even after a high-dose infusion. Although the final infusion rate was varied 80-fold from 0.025 μg/kg/min to 2μg/kg/min and the duration of anesthesia ranged from 1 to 6.8 hr, spontaneous breathing, responsiveness to voice, and extubation occurred within a few minutes in most cases. In a previous study, the pharmacokinetics of remifentanil were not greatly influenced by patient gender, weight, or age.1 Moreover, the circulating esterases responsible for remifentanil metabolism are distinct from the enzymes that metabolize succinyl-choline or acetylcholine; thus, the short duration of remifentanil may apply even in patients with deficient pseudocholinesterase activity. In addition, the pharmacokinetics of remifentanil in patients with impaired hepatic or renal function seem to be unchanged.2,3 Thus, remifentanil may offer appealing advantages as the opioid component of a balanced anesthetic when rapid emergence is desirable.

Propofol infusion and the suppression of consciousness: dose requirements to induce loss of consciousness and to suppress response to noxious and non-noxious stimuli

We have defined the infusion dose requirements of propofol to suppress consciousness and response to a variety of graded non-noxious and noxious stimuli in 52 unpremedicated patients aged 16-40 yr and 32 patients aged 41-65 yr. They were allocated to receive one of five loading dose-infusion schemes designed to establish stable conditions covering the range from wakefulness, through sedation, to loss of consciousness and anaesthesia. At 10 and 20 min after the loading dose, each patient's response to a graded series of stimuli was recorded. Probit analysis was used to derive mean values (95% confidence interval) for the ED50 and ED95 (as final infusion rate) for loss of response to verbal command at 4.9 (4.7-5.1) mg kg-1 h-1 and 7.9 (7.3-8.8) mg kg-1 h-1, respectively, in the young group and 4.2 (4.0-4.4) mg kg-1 h-1 and 5.8 (5.4-6.4) mg kg-1 h-1, respectively, in the older group. In both groups the dose-response curves for suppression of proprioception, finger counting and perception of light touch in conscious patients were shifted to the left of the curves for loss of consciousness and eyelash reflex. Dose-response curves for noxious stimuli were shifted to the right of those for loss of consciousness.

Intravenous nitroglycerine in refractory unstable angina pectoris.

Sixteen patients with severe coronary artery disease and unstable angina, refractory to standard therapy with nitrates, beta-blockers or calcium antagonists, were given intravenous nitroglycerine (500 micrograms/ml) in an open trial. The infusion was started at 0 . 17 ml/min. The final infusion rate ranged from 0 . 17 ml/min to 2 . 04 ml/min, depending on the symptomatic and haemodynamic response of the individual patient. At the slow infusion rates, the actual dose was probably only 15% of the delivered dose because of the absorption of nitroglycerine to PVC tubing. There was significant pain relief in all patients. In six patients, pain relief was complete; in ten patients, occasional episodes occurred during the nitroglycerine infusion but they were less frequent and less severe and few were associated with ST segment changes. Systolic blood pressure fell by a mean of 100 mmHg at the commencement of therapy but there was no significant change in heart rate. Apart from mild headaches, no other adverse effects were observed. The mean treatment time was 3 . 2 days (range 1-8 days). Eight patients were discharged on oral and/or cutaneous nitrate therapy and eight patients had coronary artery surgery.

Evaluation of a New Monkey Model for the Repeated Study of Bile Secretory Physiology

An unchaired monkey model for the repeated long-term study of biliary secretory physiology is reported. Postoperative management with cholre recorded. Evaluation was performed by repeated measurement, over a period of months, of bile flow and 14C erythritol clearance at three rates of taurocholate infusion given intravenously in a random order. Response to secretin was tested at the final infusion rate of taurocholate for each experiment. The outcomes of 9 monkeys were described of which 5 were repeatedly studied. They demonstrated an increase in bile flow and 14C erythritol clearance with increasing bile salt output. A dramatic choleresis over a wide range of bile salt excretion was noted with secretin and a linear relationship between bile bicarbonate output and bile salt secretion rate was observed. The new model has several major advantages and gives higher bile flows than previously recorded in the chaired model.