Low-dose Infusion Research Articles

Clinical safety and efficacy of thrombolytic therapy with low-dose prolonged infusion of tissue type plasminogen activator in patients with intermediate-high risk pulmonary embolism.

: The patients with intermediate-high risk pulmonary embolism who have acute right ventricular (RV) dysfunction and myocardial injury without overt hemodynamic compromise may be candidates for thrombolytic therapy. Alternative low-dose thrombolytic therapy strategies with prolonged infusion may further decrease the complication rates as its efficacy and safety have been previously proven in the management of prosthetic valve thrombosis. In this study, we aimed to investigate the clinical outcomes of low-dose prolonged thrombolytic therapy regimen in intermediate-high risk pulmonary embolism patients. This study enrolled 16 retrospectively evaluated patients (female 9, mean age: 70.9 ± 13.5 years) with the diagnosis of acute pulmonary embolism who were treated with low-dose and slow-infusion of tissue-type plasminogen activator (t-PA). All patients underwent transthoracic echocardiography and computed tomography scan for assessment of thrombolytic therapy success. Low-dose prolonged thrombolytic therapy was successful in all patients. The mean t-PA dose used was 48.4 ± 6.3 mg. There was residual segmental thrombus in nine (56.3%) patients after thrombolytic therapy. The arterial oxygen saturation and tricuspid annular plane systolic excursion increased after thrombolytic therapy whereas heart rate, RV to left ventricular (LV) ratio, systolic pulmonary artery pressure, and the frequencies of hypotension and tachypnea significantly decreased. There was no cerebrovascular accident or major bleeding requiring transfusion. There were two minor bleedings (12.5%) including hemoptysis and epistaxis. Thrombolytic therapy in these intermediate-high risk pulmonary embolism patients was associated with excellent clinical outcomes and survival to discharge (100%) without any 60-day mortality. Prolonged thrombolytic therapy regimen with low-dose and slow-infusion of t-PA may be associated with lower complication rates without comprimising effectiveness in patients with acute intermediate-high risk pulmonary embolism.

PSI-15 Feeding garlic powder at low doses does not negatively affect feedlot cattle health

Abstract Antimicrobial and insectifugal effects have been reported for dehydrated garlic powder. With limited knowledge of its impact on the health of beef cattle, this study investigated whether free-choice minerals infused with garlic powder affected cattle blood parameters and long-term stress during the summer. A total of 104 crossbred steers (26 steers per group) were randomly assigned to either 0% garlic product (Control), 0.3% garlic-oil-based premix (GOil), 2.5% garlic powder (2.5% GP) or 5% garlic powder (5% GP). Feed and mineral supplements were fed separately in individual GrowSafe® bunks to monitor each steer’s feed and mineral intake. Measures of individual steer performance collected include body weights and gains, feed intake and ultrasound body fat levels. Blood was collected from 10 steers with the greatest intake and 5 steers with the least mineral intake in each group for biochemical and hematological analyses. Hair samples were clipped from each steer (3 times) from the rump region to evaluate differences cortisol levels as a measure of long-term stress. Preliminary results showed no difference in final body weight (P =0.19) and dry matter intake (P =0.89). However, compared with the control, all garlic treatment groups had greater average daily mineral intake (P = 0.003). The group that received GOil had a greater average daily gain (P = 0.002) and more gain-to-feed ratio (P =0.01) than other groups. No difference (P >0.05) was observed in most serum biochemical parameters with the exception of 5% GP that had a significantly lower bilirubin (P = 0.0001) and albumin (P = 0.002) concentration but all biochemical and hematological measurements fell within the normal range for beef cattle. There was no difference (P = 0.29) among the groups for cortisol levels. The preliminary results show that low-dose infusion of garlic powder was not associated with any adverse health conditions in beef cattle.

T-cell tracking, safety, and effect of low-dose donor memory T-cell infusions after αβ T cell-depleted hematopoietic stem cell transplantation.

The delayed recovery of adaptive immunity underlies transplant-related mortality (TRM) after αβ T cell-depleted hematopoietic stem cell transplantation (HSCT). We tested the use of low-dose memory donor lymphocyte infusions (mDLIs) after engraftment of αβ T cell-depleted grafts.A cohort of 131 pediatric patients (median age 9 years) were grafted with αβ T cell-depleted products from either haplo (n = 79) or unrelated donors (n = 52). After engraftment, patients received mDLIs prepared by CD45RA depletion. Cell dose was escalated monthly from 25 × 103 to 100 × 103/kg (haplo) and from 100 × 103 to 300 × 103 /kg (MUD). In a subcohort of 16 patients, T-cell receptor (TCR) repertoire profiling with deep sequencing was used to track T-cell clones and to evaluate the contribution of mDLI to the immune repertoire.In total, 343 mDLIs were administered. The cumulative incidence (CI) of grades II and III de novo acute graft-versus-host disease (aGVHD) was 5% and 2%, respectively, and the CI of chronic graft-versus-host disease was 7%. Half of the patients with undetectable CMV-specific T cells before mDLI recovered CMV-specific T cells. TCR repertoire profiling confirmed that mDLI-derived T cells significantly contribute to the TCR repertoire up to 1 year after HSCT and include persistent, CMV-specific T-cell clones.

Using classification and regression tree modelling to investigate treatment response to a single low-dose ketamine infusion: Post hoc pooled analyses of randomized placebo-controlled and open-label trials

Background: Evidence suggests that clinical markers, such as comorbid anxiety, body weight, and others can assist in predicting response to low-dose ketamine infusion in treatment resistant depression patients. However, whether a composite of clinical markers may improve the predicted probability of response is uncertain. Methods: The current study investigated the results of our previous randomized placebo-controlled and open-label trials in which 73 patients with treatment-resistant depression (TRD) received a single ketamine infusion of 0.5 mg/kg. Clinical characteristics at baseline, including depression severity, duration of the current episode, obesity, comorbidity of anxiety disorder, and current suicide risk, were assessed as potential predictors in a classification and regression tree model for treatment response to ketamine infusion. Results: The predicted probability of a composite of age at disease onset, depression severity, duration of current episode, and obesity/overweight was significantly greater (area under curve = .736, p = .001) than that of any one marker (all p > .05). The most powerful predictors of treatment response to ketamine infusion were younger age at disease onset and obesity/overweight. The strongest predictors of treatment nonresponse were longer duration of the current episode and greater depression severity at baseline. Discussion: Depression severity, duration of the current episode, obesity, and age at disease onset may predict treatment response versus nonresponse to low-dose ketamine infusion. However, whether our predicted probability for a single infusion may be applied to repeated infusions would require further investigation. Clinical trial registration: UMIN Clinical Trials Registry (UMIN000023581 and UMIN000016985).

Happiness During Low-Dose Ketamine Infusion Predicts Treatment Response: Reexploring the Adjunctive Ketamine Study of Taiwanese Patients With Treatment-Resistant Depression.

Studies have reported that ketamine potentially increases subjective happiness in healthy volunteers. However, whether ketamine-induced happiness can predict the treatment response of ketamine infusion among patients with treatment-resistant depression (TRD) remains unknown. Between 2012 and 2015, 71 adult patients with TRD (based on DSM-IV-TR criteria) were enrolled and randomly assigned to receive a 40-minute ketamine (0.5 mg/kg or 0.2 mg/kg) or normal saline placebo infusion. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale. Measurements were conducted prior to infusion, at 40 and 240 minutes postinfusion, and, sequentially, on days 2 to 7 and 14 postinfusion. The visual analog scale for happiness (VASH) was used to assess happiness during infusion. The positive symptoms subscale of the Brief Psychiatric Rating Scale (BPRS-P) was used to measure the potential psychotomimetic effects of ketamine. For both the 2-factor (ketamine vs placebo) and 3-factor (ketamine 0.5 mg/kg vs 0.2 mg/kg vs placebo) models, a generalized estimating equation model indicated that infusion response type (happiness vs nonhappiness) significantly (P = .008 vs P = .002) predicted the trajectory of depressive symptoms after infusion. Changes in VASH and BPRS-P measures were not associated with each other. Subjective happiness during ketamine infusion predicted the antidepressant effect of both 0.5 mg/kg and 0.2 mg/kg ketamine infusion over time. Happiness during ketamine infusion, which was not related to the psychotomimetic effect of ketamine, may be associated with the reduction of depressive symptoms during the follow-up. UMIN Clinical Trials Registry registration number: UMIN000016985.

Continuous Low-Dose Heparin Infusion for Catheter-Related Thrombosis Prophylaxis in Critically-Ill Children

Introduction: Central venous catheters (CVC) are often required in critical care settings to provide life-sustaining care. Their usage has improved the quality of care in pediatric patients by providing a secure point of access which minimizes the number of peripheral needle sticks. However, CVC usage is not without risks. Children can experience acute CVC-related complications such as venous thromboembolisms (VTEs) and infections. Over the past 20 years, CVC utilization has increased and its associated complications (VTE, central line associated blood stream infection [CLABSI], catheter dysfunction) result in increased lengths of stay and hospital costs. Clinical studies identify CVCs as the single most important risk for DVT in children. Incidence rates in critically-ill children are widely divergent with historical rates of 2.7-18% and 24.7-32.5 per 1000 catheter days. In addition, other historical rates for another CVC-related complication, CLABSI, are limited but demonstrate a rate of 1.21-6.5% and 14.4 per 1000 catheter days. Prevention of catheter-related thrombosis with prophylactic anticoagulants, such as unfractionated heparin, low molecular weight heparin or warfarin, have been tested in several studies in specific subgroups of patients and the majority of studies in pediatric populations were not able to clearly demonstrate a benefit. Despite this, nearly 50% of surveyed Pediatric Intensive Care Unit (PICUs) utilize various forms and doses of heparin prophylaxis to prevent CVC-associated complications. The Penn State Health Children's Hospital PICU utilizes low dose unfractionated heparin infusions (LDUFHI) at 5-15 units/kg/hr for catheter patency and for the prevention of CVC associated complications. Methods: A retrospective chart review of all CVCs, which include non-tunneled CVC (NT-CVC), tunneled lines (TL) and peripherally inserted central catheters (PICC), utilized in the PICU at The Penn State Health Children's Hospital in 2015 was performed to determine if the usage of LDUFHI in critically ill children to maintain catheter patency results in a lower incidence of VTE and CLABSI without increasing bleeding complications in comparison to historically reported data (Beck et al.,J Pediatr. 1998;133(2):237-241; Faustino et al.,J Pediatr. 2013;162(2):387-391; Krishnaiah et al.,Pediatr Crit Care Med. 2012;13(3):e176-e180.). Results: We identified 178 subjects who had CVC which received LDUFHI in 2015. There were a total of 228 CVCs with the majority being non-tunneled CVCs (54%) followed by tunneled lines (34%) and PICCs (12%). Combined, these catheters resulted in 2086 days of use. There was a total of 5 VTEs events for an overall incidence rate of 2.19% and 2.39 per 1000 catheter days. NT-CVC had the lowest rate (1.63%) followed by TL (2.56%) and PICCs (3.7%). However, PICCs has a slightly lower rate when measuring by catheter days (NT-CVC = 2.2 per 1000 catheter days; TL = 4.01 per 1000 catheter days; PICC = 1.46 per 1000 catheter days). There were 3 CLABSI events for an incidence rate of 1.32% and 1.43 per 1000 catheter days (NT-CVC = 1.63% and 2.2 per 1000 catheter days; TL no events; PICC = 3.7% and 1.46 per 1000 catheter days). There were no episodes of heparin induced thrombocytopenia or major bleeding. Overall, the VTE and CLABSI incidence rates are dramatically lower than historical comparisons (VTE = 2.19% and 2.39 per 1000 catheter days versus 15.8-18% and 24.7-32.5 per 1000 catheter days; CLABSI = 1.32% and 1.43 per 1000 catheter days versus 6.5% and 14.4 per 1000 catheter days). In addition, this study can offer more accurate rates as incidence was also measured as a factor in catheter days. Conclusion: This study used a single tertiary pediatric intensive care site in a non-randomized fashion. These data suggest an overall lower incidence of catheter related VTE and CLABSI in critically-ill children who received LDUFHI when compared to published with comparable pediatric study populations. The incidence of complications such as CLABSI were also lower with LDUFHI usage when compared to published data involving critically ill children. The incidence rates were even lower than recently published data involving non-critically ill children. These findings suggest that a multicenter randomized study should be pursued. Disclosures No relevant conflicts of interest to declare.

Platelet Dysfunction and Persistent Fibrinolysis in Pediatric Scoliosis Surgery Patients Receiving Tranexamic Acid

High blood loss requiring transfusion is a common complication in pediatric scoliosis surgery. Bleeding in patients undergoing spinal surgery is exacerbated by the development of coagulopathy in response to extensive activation of the acute phase response (APR). Coagulopathy is characterized by consumption of coagulation factors, inflammation, and hyperfibrinolysis. Although the administration of antifibrinolytics (e.g. tranexamic acid, TXA) has significantly reduced transfusions, patients still experience high rates of blood loss, suggesting either that TXA dosing needs optimization or that plasmin-independent aspects of coagulopathy could be driving bleeding. Major orthopedic surgeries are characterized by a reduction in platelet counts indicating the coagulopathic conditions of surgery exert a tropism on the circulating platelet population. Indeed, platelet dysfunction concomitant with trauma-induced coagulopathy has been extensively described in literature. Platelet dysfunction during adult orthopedic surgery has been observed but has not been correlated with bleeding, and platelet function in pediatric spine surgery has yet to be assessed. To determine if pediatric patients also experience platelet dysfunction, we measured platelet activation by whole blood flow cytometry during the course of scoliosis surgery in 8 pediatric patients. In parallel, circulating markers of the APR (i.e. IL-6, IL-10, IL-8), products of fibrinolysis (D-dimer), and indicators of consumptive coagulopathy (Protein C) were measured by multiplex ELISA. Samples were collected preoperatively (Preop), intraoperatively (every 2 hours, Intraop 1 and Intraop 2), immediately after closure (Postop) and the following morning (POD1). Samples were stimulated with submaximal concentrations of thrombin, convulxin (GPVI agonist, collagen receptor), and ADP. Platelet integrin activation was measured by PAC1 binding (GPIIbIIIa activation) and platelet secretion was measured by CD62p binding (P-selectin surface expression). We observed a progressive and statistically significant reduction in the platelet response (GPIIbIIIa activation and P-selectin expression) to both thrombin and convulxin stimulation during the procedure but with distinct temporal patterns. The reduction in response to thrombin became significant at Postop, remaining down even at POD1 (PAC1 max reduction, Postop 1: 32.5%, p=0.0403; P-selectin max reduction, POD1: 33.9%, p=0.016). The reduction in response to convulxin, on the other hand developed almost immediately after the initiation of surgery, starting with Intraop1 and resolving by Postop (PAC1 max reduction, Intraop 1: 25.1%, p=0.0087; P-selectin max reduction, Intraop 1: 18.3%, p=0.0369). Intra-operative responses to thrombin (both PAC1 and CD62p binding) significantly correlated with estimates of blood loss based on red blood cell mass (Estimated Red Blood Cell Mass, ERCM def) and hemoglobin mass (Hg mass loss) (see Table I below). Although we observed a consistent and statistically significant reduction in platelet number it correlated with blood loss at POD1 only, suggesting platelet function is a better predictor of blood loss than platelet count. Despite all patients receiving a bolus of TXA with continuous low dose infusion, multiplex results indicated a progressive increase in circulating D-dimer, becoming statistically significant at Postop and persisting through POD 1. Elevations in D-dimer, the byproduct of plasmin degradation of fibrin, suggest elusive fibrinolysis despite administration of TXA. Significant intraoperative elevations in IL-6, IL-10, and IL-8 and consumption of Protein C were also noted that persisted through POD1, indicating the development of coagulopathy. In conclusion, pediatric scoliosis surgery is characterized by persistent fibrinolysis platelet dysfunction, activation of the APR, and coagulopathy despite administration of the anti-fibrinolytic TXA. Future studies will focus on altering the dose of TXA to determine if an optimal dosing can be achieved that effectively inhibits fibrinolysis and answer important questions about the dependence of the APR and platelet hypofunction on the persistent fibrinolysis seen in these patients. Figure Disclosures No relevant conflicts of interest to declare.

CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Relapsed/Refractory Multiple Myeloma

CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Relapsed/Refractory Multiple Myeloma

Activation of the 5-HT7 receptor but not nitric oxide synthase is necessary for chronic 5-hydroxytryptamine-induced hypotension.

What is the central question of this study? What mechanisms account for the hypotension observed during chronic elevations in circulating 5-hydroxytryptamine in rats? What is the main finding and its importance? Chronic 5-hydroxytryptamine-induced hypotension requires continued activation of the 5-HT7 receptor subtype but does not require NO, an outcome that resolves previous conflicting results. Therapeutic interruption of the hypotensive actions of 5-HT under pathophysiological conditions can only be achieved through blockade of the 5-HT7 receptor. Low dose infusion of 5-hydroxytryptamine (5-HT) to rats causes both an acute and a chronic fall in arterial blood pressure. The 5-HT7 receptor subtype plays a critical part in the observed hypotension. Acute (minutes to hours) 5-HT infusion shows no depressor role for nitric oxide (NO), but 5-HT depressor responses under chronic conditions suggest that NO production may be critical. We test the hypothesis that NO contributes to the chronic, but not the acute, depressor response to 5-HT. We compared the role of NO and 5-HT7 receptors in 5-HT-induced hypotension under acute and chronic conditions in the same animal. Mean arterial pressure and heart rate were measured by radiotelemetry in conscious rats during 5days of saline or 5-HT (25μgkg-1 min-1 ; osmotic pump) infusion and for 2days after infusion was stopped. To quantify the contributions of NO and the 5-HT7 receptor to 5-HT-induced hypotension, the nitric oxide synthase (NOS) inhibitor l-NAME or the selective 5-HT7 receptor antagonist SB-267790 were given at 1, 3 and 5days of chronic infusion, and 1 day after 5-HT infusion pumps were removed. Nω -Nitro-l-arginine methyl ester (l-NAME) caused a pressor response of the same magnitude in the absence or presence of 5-HT infusion. Conversely, SB-269970 did not affect mean arterial pressure in the absence of 5-HT infusion and reversed the 5-HT-induced depressor response at each time point. Our findings demonstrate that acute and chronic 5-HT-induced hypotension does not require NOS activation but does require continued activation of the 5-HT7 receptor.

Fibrinolysis in left-sided mechanical prosthetic valve thrombosis with high INR.

A significant number of patients with prosthetic valve thrombosis have a prothrombin time international normalised ratio in the therapeutic range at presentation. Surgery may not be possible in many patients and traditionally a high international normalised ratio is considered a relative contraindication for fibrinolysis. We conducted an observational study in patients with left-sided obstructive prosthetic valve thrombosis with international normalised ratio at or above the therapeutic range at presentation who received fibrinolysis. The fibrinolytic regimens, timing of initiation, success of fibrinolysis, risk of major and minor bleeding and ischaemic stroke were evaluated in the study. Of 30 patients included in the study 70% received immediate fibrinolysis and in 30% it was delayed. The majority of patients (90%) presented with New York Heart Association class III/IV symptoms. The mean international normalised ratio at fibrinolysis was 3.04 ± 0.70 in the immediate group and 2.42 ± 0.89 in the delayed group. Haemodynamically stable patients who had delayed initiation of fibrinolysis had a trend towards less bleeding without an increase in mortality. The rates of intracranial haemorrhage (0% vs. 7.7%), minor bleeding (12.5% vs. 25.1%) and ischaemic stroke (0% vs. 30.7%) were lower in patients who received low dose infusion compared to a conventional dose. Fibrinolysis can be considered in patients with prosthetic valve thrombosis with high international normalised ratio at presentation. For haemodynamically stable patients, delayed initiation of fibrinolysis is associated with a marginally lower bleeding risk without an increase in mortality. Low dose infusion may be considered over a conventional dose as it is associated with a lower incidence of ischaemic stroke and a good rate of valve function restoration with a trend towards less bleeding.

Is Unfavourable Cervix prior to Labor Induction Risk for Adverse Obstetrical Outcome in Time of Universal Ripening Agents Usage? Single Center Retrospective Observational Study.

Cervical assessment on the Bishop scale prior to induction of labor (IOL) is one of the strongest prognostic criteria in relation to the success of the procedure. The commonly used preinduction methods are mainly aimed at reducing the percentage of cesarean sections. Our study has analyzed obstetric results of patients who had unripe cervix (Bishop score <7) before IOL and used preinduction (Foley catheter or misoprostol vaginal insert releasing 7 mcg of misoprostol per hour for 24 hours) with obstetric results of patients in whom, due to favourable cervix, only a low-dose infusion of oxytocin was used. We reviewed the medical records of 1010 single pregnancies in whom IOL was performed. We divided the patients into two groups: group A (where preinduction was used) and group B (Bishop score ≥7 points) where preinduction was not used. Patients in group A were more likely to complete the delivery by caesarean section (OR = 4.58, 95% CI 3.22-6.51), and more likely to have events that were indications for operative delivery: unreassuring fetal heart rate trace (OR = 3.29, 95% CI 2.07-5.23) and arrested labor or failed induction (OR = 3.4, 95% CI 2.06-5.62). The groups did not differ in the percentage of vacuum extraction, postpartum haemorrhage, and meconium stained amniotic fluid. In group B, more infants were born with umbilical cord blood pH <7.1 (1.38% vs. 0%), both groups included no deliveries of newborns with Apgar score ≤3 points, the groups did not differ in terms of the percentage of newborns with Apgar score between 4 and 7 at birth (OR = 0.66, 95% CI 0.29-1.49). The immature cervix and the need to use labor preinduction is a risk factor for caesarean section. The necessity of preinduction does not impair neonatological results.

A prospective observational study on efficacy of serial low dose infusion of rituximab (500 mg) on patients of pemphigus

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody being increasingly used in management of pemphigus. Various studies show a lack of any uniform treatment protocol. The objective of the study was to assess the effectiveness of RTX in patients of pemphigus receiving serial low doses of RTX (500 mg; maximum of 4 doses; 2 weeks apart).&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods: &lt;/strong&gt;It was a prospective observational review of 40 pemphigus patients to assess the proportion of patients achieving complete remission after serially receiving low dose RTX, time and number of doses required to achieve complete remission (CR), proportion of patients who responded partially or didn’t respond or relapsed after achieving CR. Additionally, the study was done to find whether a correlation existed between age, gender, and site of lesion and RTX administration.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results: &lt;/strong&gt;40 pemphigus patients followed up for a mean duration (MD) of 174.15±95.67 days received 4 doses of RTX (500 mg) irrespective of the disease activity 0.30 (75%) attained CR on therapy with ≥3 doses of RTX 500 mg (MD= 76.39±34.45 days) and azathioprine 100 mg/day. No patients relapsed after 4 doses while 3 (7.5%) patients didn’t respond. Oral lesions and pemphigus vulgaris took more time for achieving CR.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;While we reinforce the idea of using more than 3 doses of RTX 500 mg in a view to achieve prolonged remission we promote considering usage of a more cost-effective drug like azathioprine for maintaining remission especially in a poor remote tertiary center in India with limited resources. Immunological assays were not performed limiting the study.&lt;/p&gt;

A Combination of Inhaled Nitrous Oxide and Low-Dose Ketamine Infusion for Labor Analgesia

(J Clin Anesth. 2019;57:64–65) While ketamine is useful in a labor analgesia setting, it is typically used infrequently due to its association with lower Apgar scores, uterine hypertonus, and maternal psychological reactions. Inhaled nitrous oxide (iNO) is another analgesia option, although it provides maternal anxiolytic effects but limited labor analgesia. Not much research has been done on using the combination of a low-dose ketamine infusion (&lt;0.5 mg/kg/h intravenous) and iNO for labor analgesia. These authors outlined 2 cases that apply this analgesic regimen.

Generalizability of Randomized Trials of the Programmed Intermittent Epidural Bolus Technique for Maintenance of Labor Analgesia: A Prospective Single-Centre Cohort Study

(Br J Anaesth. 2019;123:e434–e441) Neuraxial analgesia is the most widely used labor pain relief method, and patient-controlled epidural analgesia (PCEA) used in combination with a low-dose continuous epidural infusion has been shown to boost patient satisfaction while also increasing the volume of local anesthetics that are used. Researchers who have conducted randomized controlled trials (RCTs) have shown that substituting a programmed intermittent epidural bolus (PIEB) in place of PCEA can decrease local anesthetic consumption, but it is unclear if the maternal motor block in this method has a negative effect on labor progression. Because RCTs are almost always conducted on healthy nulliparous women, their results cannot easily be applied to the variety of patients seen in daily clinical practices. Gabriel and colleagues conducted their study on epidural labor analgesia data in order to compare the maternal motor function of RCT-eligible nulliparous women to parous women who are usually considered RCT-ineligible.

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee.

Purpose:Established tonic–clonic status epilepticus (SE) does not stop in one-third of patients when treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM). These patients have refractory status epilepticus (RSE) and a high risk of morbidity and death. For patients with convulsive refractory status epilepticus (CRSE), we sought to determine the strength of evidence for 8 parenteral ASMs used as third-line treatment in stopping clinical CRSE.Methods:A structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) was performed to identify original studies on the treatment of CRSE in children and adults using IV brivaracetam, ketamine, lacosamide, levetiracetam (LEV), midazolam (MDZ), pentobarbital (PTB; and thiopental), propofol (PRO), and valproic acid (VPA). Adrenocorticotropic hormone (ACTH), corticosteroids, intravenous immunoglobulin (IVIg), magnesium sulfate, and pyridoxine were added to determine the effectiveness in treating hard-to-control seizures in special circumstances. Studies were evaluated by predefined criteria and were classified by strength of evidence in stopping clinical CRSE (either as the last ASM added or compared to another ASM) according to the 2017 American Academy of Neurology process.Results:No studies exist on the use of ACTH, corticosteroids, or IVIg for the treatment of CRSE. Small series and case reports exist on the use of these agents in the treatment of RSE of suspected immune etiology, severe epileptic encephalopathies, and rare epilepsy syndromes. For adults with CRSE, insufficient evidence exists on the effectiveness of brivaracetam (level U; 4 class IV studies). For children and adults with CRSE, insufficient evidence exists on the effectiveness of ketamine (level U; 25 class IV studies). For children and adults with CRSE, it is possible that lacosamide is effective at stopping RSE (level C; 2 class III, 14 class IV studies). For children with CRSE, insufficient evidence exists that LEV and VPA are equally effective (level U, 1 class III study). For adults with CRSE, insufficient evidence exists to support the effectiveness of LEV (level U; 2 class IV studies). Magnesium sulfate may be effective in the treatment of eclampsia, but there are only case reports of its use for CRSE. For children with CRSE, insufficient evidence exists to support either that MDZ and diazepam infusions are equally effective (level U; 1 class III study) or that MDZ infusion and PTB are equally effective (level U; 1 class III study). For adults with CRSE, insufficient evidence exists to support either that MDZ infusion and PRO are equally effective (level U; 1 class III study) or that low-dose and high-dose MDZ infusions are equally effective (level U; 1 class III study). For children and adults with CRSE, insufficient evidence exists to support that MDZ is effective as the last drug added (level U; 29 class IV studies). For adults with CRSE, insufficient evidence exists to support that PTB and PRO are equally effective (level U; 1 class III study). For adults and children with CRSE, insufficient evidence exists to support that PTB is effective as the last ASM added (level U; 42 class IV studies). For CRSE, insufficient evidence exists to support that PRO is effective as the last ASM used (level U; 26 class IV studies). No pediatric-only studies exist on the use of PRO for CRSE, and many guidelines do not recommend its use in children aged <16 years. Pyridoxine-dependent and pyridoxine-responsive epilepsies should be considered in children presenting between birth and age 3 years with refractory seizures and no imaging lesion or other acquired cause of seizures. For children with CRSE, insufficient evidence exists that VPA and diazepam infusion are equally effective (level U, 1 class III study). No class I to III studies have been reported in adults treated with VPA for CRSE. In comparison, for children and adults with established convulsive SE (ie, not RSE), after an initial benzodiazepine, it is likely that loading doses of LEV 60 mg/kg, VPA 40 mg/kg, and fosphenytoin 20 mg PE/kg are equally effective at stopping SE (level B, 1 class I study).Conclusions:Mostly insufficient evidence exists on the efficacy of stopping clinical CRSE using brivaracetam, lacosamide, LEV, valproate, ketamine, MDZ, PTB, and PRO either as the last ASM or compared to others of these drugs. Adrenocorticotropic hormone, IVIg, corticosteroids, magnesium sulfate, and pyridoxine have been used in special situations but have not been studied for CRSE. For the treatment of established convulsive SE (ie, not RSE), LEV, VPA, and fosphenytoin are likely equally effective, but whether this is also true for CRSE is unknown. Triple-masked, randomized controlled trials are needed to compare the effectiveness of parenteral anesthetizing and nonanesthetizing ASMs in the treatment of CRSE.

Functional Dysconnectivity of Frontal Cortex to Striatum Predicts Ketamine Infusion Response in Treatment-Resistant Depression.

BackgroundFrontostriatal disconnectivity plays a crucial role in the pathophysiology of major depressive disorder. However, whether the baseline functional connectivity of the frontostriatal network could predict the treatment outcome of low-dose ketamine infusion remains unknown.MethodsIn total, 48 patients with treatment-resistant depression were randomly divided into 3 treatment groups (a single-dose 40-minute i.v. infusion) as follows: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and saline placebo infusion. Patients were subsequently followed-up for 2 weeks. Resting-state functional magnetic resonance imaging was performed for each patient before infusion administration. In addition, the baseline frontostriatal functional connectivity of patients with treatment-resistant depression was also compared with that of healthy controls.ResultsCompared with the healthy controls, patients with treatment-resistant depression had a decreased functional connectivity in the frontostriatal circuits, especially between the right superior frontal cortex and executive region of the striatum and between the right paracingulate cortex and rostral-motor region of the striatum. The baseline hypoconnectivity of the bilateral superior frontal cortex to the executive region of the striatum was associated with a greater reduction of depression symptoms after a single 0.2-mg/kg ketamine infusion.ConclusionReduced connectivity of the superior frontal cortex to the striatum predicted the response to ketamine infusion among patients with treatment-resistant depression.

Postoperative analgesic efficacy of modified continuous transversus abdominis plane block in laparoscopic colorectal surgery: a triple-blind randomized controlled trial

The optimal opioid-sparing analgesic regimen following laparoscopic colorectal surgery (LCS) remains uncertain. We sought to determine the efficacy of low-dose bupivacaine infusion via surgeon-inserted modified continuous transversus abdominis plane (mcTAP) catheters after LCS. A parallel-group, placebo-controlled, randomized single-centre trial was conducted between April 2017 and February 2018. Block-of-four randomization and allocation concealment by sequentially-numbered, opaque sealed envelopes were used. Patients, surgeons and assessors were blinded. Fifty-two patients were randomized to receive either 0.2% bupivacaine or saline through mcTAP catheters. A 5ml bolus followed by a 72h infusion at 2ml/h was started, with patient-controlled fentanyl analgesia and oral paracetamol given on demand. Primary outcomes were fentanyl consumptions in the first 24h, second 24h, and third 24h following surgery. Secondary outcomes were pain numeric rating scores, recovery outcomes and complications. Twenty-five patients in the bupivacaine group and 26 in the control group were analysed. Patients in the bupivacaine group required significantly less fentanyl overall (106.1 vs 484.5 mcg, p < 0.001) and at all time points (first 24h: 61.0 vs 324.3 mcg, p < 0.001; second 24h: 36.3 vs 119.0 mcg, p = 0.033; third 24h: 8.8 vs 41.2, p = 0.030) when compared to placebo. Significantly lower pain scores at rest at 6h (2.32 vs 4.0, p = 0.002), and 12h (1.80 vs 3.08, p = 0.011) and on coughing at 6h (4.56 vs 5.84, p = 0.019), 12h (3.76 vs 4.96, p = 0.009), and 24h (3.44 vs 4.24, p = 0.049) as well as significantly lower opioid-related complications such as nausea or vomiting (9 (36%) vs 1 (4%), p =0.005) were observed in the bupivacaine group. There were no major block-related complications, and recovery outcomes were similar in both groups. McTAP block reduces postoperative fentanyl consumption and pain scores after LCS, highlighting its role as a safe and useful opioid-sparing analgesia. TCTR20150831001 (Thai Clinical Trials Registry). Full trial protocol can be assessed at https://www.clinicaltrials.in.th/ .

Effect of the p38 MAPK inhibitor doramapimod on the systemic inflammatory response to intravenous lipopolysaccharide in horses.

BackgroundDoramapimod, a p38 MAPK inhibitor, is a potent anti‐inflammatory drug that decreases inflammatory cytokine production in equine whole blood in vitro. It may have benefits for treating systemic inflammation in horses.ObjectiveTo determine whether doramapimod is well tolerated when administered IV to horses, and whether it has anti‐inflammatory effects in horses in a low‐dose endotoxemia model.AnimalsSix Standardbred horses.MethodsTolerability study, followed by a blinded, randomized, placebo‐controlled cross‐over study. Horses were given doramapimod, and clinical and clinicopathological variables were monitored for 24 hours. Horses then were treated with doramapimod or placebo, followed by a low dose infusion of lipopolysaccharide (LPS). Clinical variables (heart rate, rectal temperature, noninvasive blood pressure), leukocyte count and tumor necrosis factor alpha (TNF‐α) and interleukin‐1 beta (IL‐1β) concentrations were measured at multiple time points until 6 hours post‐LPS infusion.ResultsNo adverse effects or clinicopathological changes were seen in the safety study. When treated with doramapimod as compared to placebo, horses had significantly lower heart rates (P = .03), rectal temperatures (P = .03), and cytokine concentrations (P = .03 for TNF‐α and IL‐1β), and a significantly higher white blood cell count (P = .03) after LPS infusion.Conclusions and Clinical ImportanceDoramapimod has clinically relevant anti‐inflammatory effects in horses, likely mediated by a decrease in leukocyte activation and decrease in the release of pro‐inflammatory cytokines. To evaluate its potential as a novel treatment for systemic inflammatory response syndrome in horses, clinical trials will be necessary to determine its efficacy in naturally occurring disease.

THE EFFECT OF LOW-DOSE INTRAVESICAL BACILLUS CALMETTE-GUÉRIN (BCG) INFUSION THERAPY FOR NON-MUSCLE INVASIVE BLADDER CANCER

(Objective) Bacillus Calmette-Guérin (BCG) intravesical infusion therapy plays an important role in the treatment of patients with high-risk non-muscle-invasive bladder cancer (NMIBC). Our institute performs low-dose (40 mg) BCG intravesical infusion therapy (completed 8 times) to reduce side effects. We retrospectively investigated its efficacy and side effects. (Patients and methods) We analyzed the response, non-recurrence, and side effect rates by risk stratification in 179 patients who received low-dose BCG intravesical infusion therapy from September 2003 to November 2018 in Nagano Municipal Hospital. Complications were classified using the Common Terminology Criteria for Adverse Events version 4.0. (Results) The median age was 73 years, and the male/female ratio was 137:42. The median observation period was 32 months, and infusion was completed 8 times in 149 cases (83.2%). The overall response rate was 88.8%. The response rate was significantly higher in the low-grade pathology group than in the high-grade group. However, no significant differences in G1/G2/G3 side effects, sex, age, presence of carcinoma in situ (CIS), depth of invasion, purpose of administration, and grade of side effects were observed. The overall non-recurrence rates were 91.8%, 76.7%, and 71.3% at 1, 3, and 5 years, respectively. Nevertheless, there were no significant differences in the non-recurrence rates with respect to depth of penetration, the degree of dysmorphism, purpose of administration, presence of CIS, and completed of infusion. A total of 71 G2 side effects (39.7%) were identified, and 3 cases of G3 side effects required hospitalization. (Conclusion) In our institution, the completion rate of low-dose BCG intravesical infusion therapy was high, with few side effects. Furthermore, it demonstrated similar therapeutic effect to that reported with standard-dose administration. Low-dose BCG intravesical infusion therapy may be an effective treatment, particularly for pathologically low-grade NMIBC.

Pilot randomized active-placebo-controlled trial of low-dose ketamine for the treatment of multiple sclerosis–related fatigue

Background: Fatigue is the most common symptom of MS and has no effective pharmacotherapy. Objective: To determine the tolerability, safety, and efficacy of low-dose ketamine infusion for MS-related fatigue. Methods: In this double-blind, randomized, active-placebo-controlled trial, 18 subjects with multiple sclerosis (MS) and reported fatigue received a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.05 mg/kg). The primary outcome was change in Daily Fatigue Severity (DFS) for 7 days following the infusion. Secondary outcomes included Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) measured up to day 28 post-infusion. We analyzed changes in all outcomes using mixed-effect models. Results: In total, 18 participants were enrolled; 67% participants received ketamine. Side effects of ketamine were transient. No change in the DFS was observed after 7 days (−0.10 point; 95% confidence interval (CI): −0.32, 0.12; p = 0.40). We observed a trend in reduced FSS scores at 1 week (−5.2 points; 95% CI: −10.4, 0.14; p = 0.06) and a clinically and statistically significant reduction in MFIS score at day 28 (−13.5 point; 95% CI: −25.0, −1.98; p = 0.04). Conclusions: Ketamine infusions were safe and well-tolerated. While no change in DFS after 7 days was observed, secondary analyses suggest a benefit of ketamine infusion for reduction of longer term fatigue severity in people with MS.