Low-dose Continuous Infusion Research Articles

Effect of low-dose norepinephrine combined with goal-directed fluid therapy on postoperative pulmonary complications in lung surgery: A prospective randomized controlled trial

Study objectivePostoperative pulmonary complications (PPCs), the predominant complications following lung surgery, are closely associated with intraoperative fluid therapy. This study investigates whether continuous low-dose norepinephrine infusion combined with goal-directed fluid therapy (GDFT) reduced the risk of PPCs after lung surgery relative to either GDFT alone or standard fluid treatment. DesignA prospective, randomized controlled trial. SettingThe First Affiliated Hospital of Anhui Medical University, Anhui, China. PatientsThe study included 184 patients undergoing elective thoracoscopic lung resection surgery. InterventionsPatients were randomized into three groups based on different fluid treatment regimens: Group C received standard fluid treatment, Group G received GDFT, and Group N received continuous low-dose norepinephrine infusion combined with GDFT. MeasurementsThe primary outcome was the incidence of PPCs, including respiratory infection, atelectasis, pneumothorax, pleural empyema, respiratory failure, pulmonary embolism and bronchopleural fistula, during the postoperative hospital stay. Secondary outcomes were hemodynamic variables and arterial blood gases. Additional recorded parameters included other postoperative complications such as bleeding, postoperative re-intubation, re-hospitalization within 30 days, and the length of hospital stay. Main resultsGroup N showed a significantly lower PPCs incidence during hospitalization compared to Group C (11.5 % vs 27.9 %; odds ratio, 2.98; 95 % confidence interval, 1.17–8.31; P = 0.023). No significant difference in PPCs was found between Group N and Group G (11.5 % vs 14.5 %; odds ratio, 1.31; 95 % confidence interval, 0.46–3.91; P = 0.616). Additionally, there were no significant differences among the three groups in the components of PPCs. Group N showed higher mean arterial pressure and stroke volume index intraoperatively compared to Group C. ConclusionsContinuous low-dose norepinephrine infusion combined with GDFT reduced PPCs incidence in elective lung surgery patients compared with standard fluid management, but showed no difference compared to GDFT alone. Clinical trial registrationChiCTR2200064081.

8281 Continuous Low-Dose Etomidate Infusion For The Management Of Severe Hypercortisolism In Metastatic Adrenocortical Carcinoma

Abstract Disclosure: A. Jamil: None. N. Mohammad: None. S. Narayana: None. Background: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal glands with a poor prognosis that often presents with excess hormone secretion. Approximately, 45% of cases present with hypercortisolism.1 A key component of management is achieving control of hypercortisolism. Though there are multiple enteral therapies that can inhibit cortisol production, few treatment options are available for use in critically ill patients who are not surgical candidates and cannot take oral medications. Though primarily known as a short-acting intravenous anesthetic agent used for sedation, etomidate also inhibits 11-β-hydroxylase, a key enzyme involved in corticosteroid biosynthesis.2 Clinical Case: A 28-year-old woman with metastatic adrenocortical carcinoma with associated hypercortisolism was initially admitted for anemia and thrombocytopenia, with an initial cortisol on admission of 29.3 μg/dl (normal range: 2.3-19.4 ug/dl). Due to her large tumor burden with metastasis to the liver and invasion into the inferior vena cava, she was deemed a poor surgical candidate with a poor overall prognosis. Her hospital course was complicated by acute hypoxemic respiratory failure requiring intubation, and thus her enteral steroidogenesis inhibitors (mitotane, ketoconazole, and metyrapone) were discontinued as none were administrable via nasogastric tube. Consequently, her hypercortisolism worsened rapidly with a cortisol level of 351.3 μg/dl , prompting initiation of continuous low-dose etomidate infusion, which resulted in significant improvements in her cortisol levels. After eight days of etomidate treatment, her cortisol levels reached a goal value of 25.0 μg/dl. However, she then suffered an ischemic cerebrovascular event and multiorgan failure, and was subsequently transitioned to hospice care. Conclusion: Low-dose etomidate infusion is an effective therapeutic agent for hypercortisolism in patients with ACC that are unable to take oral medications.

Real-world comparison of low- versus high-dose continuous 5FU infusion in patients receiving triplet chemotherapy plus bevacizumab for newly diagnosed metastatic colorectal cancer (mCRC).

62 Background: Several randomized trials demonstrated an overall survival (OS) benefit to triplet chemotherapy (5-FU, oxaliplatin, and irinotecan) plus bevacizumab compared to doublet chemotherapy plus bevacizumab in patients with newly diagnosed mCRC, though with higher rates of neutropenic fever and diarrhea. These trials used high-dose continuous infusion 5-FU (3,200 mg/m2/48 hours), but national guidelines suggest low-dose continuous infusion 5-FU (2,400mg/m2/48 hours) due to lower tolerance in U.S. patients. We performed a retrospective cohort study in a U.S. population to compare the effectiveness of low- vs high-dose continuous infusion 5FU in patients undergoing triplet chemotherapy plus bevacizumab for newly diagnosed mCRC. Methods: We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data curated via technology-enabled abstraction from ~280 cancer clinics. Patients with newly diagnosed mCRC who initiated triplet chemotherapy plus bevacizumab between 10/23/14 and 10/31/22 with non-missing height, weight, and dosing data were included. 5FU infusion doses of 2,000 – 2,799 mg/m2 were categorized as low-dose while those >/= 2,800 mg/m2 were categorized as high-dose. OS from first-line treatment initiation was assessed by dosing group using the Kaplan Meier method with log-rank testing. Multivariable analysis with adjustment for pre-specified variables with imbalance (defined by standardized difference < - 0.10 or > 0.10) was performed using multivariable Cox proportional hazards modeling. Missing data were imputed using multiple imputation with chained equations. Results: Among 320 patients included, 244 received low-dose and 76 patients received high-dose continuous infusion 5FU. Imbalance between low- and high-dose groups was observed in the use of 5FU bolus (23% vs 3%), year of metastatic diagnosis 2018 - 2022 (80% vs 55%), mean irinotecan dose (156.4 vs 160.5 mg/m2), left-sided primary (73% vs 64%), MMR deficiency (3% vs 6%) and mean CEA (478 vs 691 µg/L). In univariate analysis, median OS was 33 months (95% CI 26 – 39) in the low-dose group compared to 34 months (95% CI 24 – 48) in the high-dose group (HR 1.16; 95% CI 0.79 – 1.69; p = 0.44). After adjusting for imbalanced covariates, there was no difference in hazard of death between low- and high-dose groups (HR 0.99; 95% CI 0.64 – 1.53; p = 0.97). Conclusions: In this real-world, U.S. population with newly diagnosed mCRC receiving triplet chemotherapy plus bevacizumab, there was no association with survival between low- vs high-dose continuous infusion 5FU. This supports current guidelines recommending low-dose continuous infusion 5FU (2,400mg/m2/48 hours) for patients with mCRC receiving triplet chemotherapy in the U.S.

Comparison of Norepinephrine & Terlipressin vs Norepinephrine Alone for Management for Septic Shock

Introduction: Sepsis is a clinical syndrome that has physiologic, biologic, and biochemical abnormalities caused by a dysregulated inflammatory response to infection. The present study aimed to estimate the dose of injection of norepinephrine in micrograms/ kg/min after 12 hours of starting the vasopressor infusion to keep an MAP of above 65 mm Hg. Materials & Method: The study was done for the period of two years. Patients who were 18 years and above; who were diagnosed with septic shock during their ICU course and whose relatives gave informed written consent were included in the study. Result: Total of 12 patients were lost during the study period and so in total 100 patients were enrolled for the study. Both the groups were comparable with respect to the MAP (p = 0.655). The norepinephrine dose in group I vs group II at 12 hours was found to be 0.163 ± 0.089 vs 0.396 ± 0.18 μg/kg/min (p <0.001). Reduction in blood lactate concentration in 12 hours was significantly higher in group I [1.479 ± 1.46] than group II [0.08 ± 1.50] mmol/L (p = 0.002). Increase in the urine output of the patients in 12 hours in Group I [0.72 ± 0.44] than group II [0.47 ± 0.460] mL/kg/hour (p = 0.001). Conclusion: A low-dose continuous infusion of terlipressin may have a significant role in ensuring better organ perfusion, preventing renal injury, and improving the SOFA score of the patients when used in adjunct to norepinephrine, early in the management of septic shock.

An anesthesia protocol for robust and repeatable measurement of behavioral visceromotor responses to colorectal distension in mice.

Visceral motor responses (VMR) to graded colorectal distension (CRD) have been extensively implemented to assess the level of visceral pain in awake rodents, which are inevitably confounded by movement artifacts and cannot be conveniently implemented to assess invasive neuromodulation protocols for treating visceral pain. In this report, we present an optimized protocol with prolonged urethane infusion that enables robust and repeatable recordings of VMR to CRD in mice under deep anesthesia, providing a two-hour window to objectively assess the efficacy of visceral pain management strategies. During all surgical procedures, C57BL/6 mice of both sexes (8-12 weeks, 25-35 g) were anesthetized with 2% isoflurane inhalation. An abdominal incision was made to allow Teflon-coated stainless steel wire electrodes to be sutured to the oblique abdominal musculature. A thin polyethylene catheter (Φ 0.2 mm) was placed intraperitoneally and externalized from the abdominal incision for delivering the prolonged urethane infusion. A cylindric plastic-film balloon (Φ 8 mm x 15 mm when distended) was inserted intra-anally, and its depth into the colorectum was precisely controlled by measuring the distance between the end of the balloon and the anus. Subsequently, the mouse was switched from isoflurane anesthesia to the new urethane anesthesia protocol, which consisted of a bout of infusion (0.6 g urethane per kg weight, g/kg) administered intraperitoneally via the catheter and continuous low-dose infusion throughout the experiment at 0.15-0.23 g per kg weight per hour (g/kg/h). Using this new anesthesia protocol, we systematically investigated the significant impact of balloon depth into the colorectum on evoked VMR, which showed a progressive reduction with increased balloon insertion depth from the rectal region into the distal colonic region. Intracolonic TNBS treatment induced enhanced VMR to CRD of the colonic region (>10 mm from the anus) only in male mice, whereas colonic VMR was not significantly altered by TNBS in female mice. Conducting VMR to CRD in anesthetized mice using the current protocol will enable future objective assessments of various invasive neuromodulatory strategies for alleviating visceral pain.

Ketamine use for management of vaso-occlusive pain in pediatric sickle cell disease.

Typical sickle cell disease (SCD) vaso-occlusive pain episode (VOE) management includes opioids, which are often inadequate and can be associated with significant side effects. Ketamine, a dissociative anesthetic, is a potentially effective adjunct to VOE management. This study aimed to characterize ketamine use for VOE management in pediatric SCD. This retrospective case series summarizes a single-center experience regarding the use of ketamine for inpatient management of pediatric VOE in 156 admissions from 2014 to 2020. Continuous low-dose ketamine infusion was most commonly prescribed to adolescents and young adults as an adjunct to opioids (median starting dose 2.0μg/kg/min; median maximum dose 3.0μg/kg/min). Ketamine was started a median of 13.7hours after admission. Median ketamine infusion duration was 3days. In most encounters, ketamine infusion was discontinued prior to opioid patient-controlled analgesia (PCA) discontinuation. The majority of encounters (79.3%) had a reduction in either PCA dose, continuous opioid infusion, or both while receiving ketamine. Low-dose ketamine infusion was associated with side effects noted in 21.8% (n=34) of encounters. The most common side effects included dizziness (5.6%), hallucinations (5.1%), dissociation (2.6%), and sedation (1.9%). There were no reports of ketamine withdrawal. Most patients who received ketamine went on to receive it again during a subsequent admission. Further study is needed to determine the optimal timing of ketamine initiation and dosing. The variability of ketamine administration highlights the need for standardized protocols for ketamine use in VOE management.

The role of flumazenil in generalised anxiety disorder: a pilot naturalistic open-label study with a focus on treatment resistance

Anxiety disorders are highly prevalent and chronic disorders with treatment resistance to current pharmacotherapies occurring in approximately one in three patients. It has been postulated that flumazenil (FMZ) is efficacious in the management of anxiety disorders via the removal of α4β2δ gamma-aminobutyric acid A receptors. To assess the safety and feasibility of continuous low-dose FMZ infusions for the management of generalised anxiety disorder (GAD) and collect preliminary efficacy data. Uncontrolled, open-label pilot study. Participants had a primary diagnosis of generalised anxiety disorder (GAD) and received two consecutive subcutaneous continuous low-dose FMZ infusions. Each infusion contained 16 mg of FMZ and was delivered over 96 ± 19.2 h. The total dose of FMZ delivered was 32 mg over approximately 8 days. Sodium valproate was given to participants at risk of seizure. The primary outcome was the change in stress and anxiety subscale scores on the Depression Anxiety Stress Scale-21 between baseline, day 8, and day 28. Nine participants with a primary diagnosis of GAD were treated with subcutaneous continuous low-dose FMZ infusions; seven participants met the criteria for treatment resistance. There was a significant decrease in anxiety and stress between baseline and day 8 and baseline and day 28. There was also a significant improvement in subjective sleep quality from baseline to day 28 measured by the Jenkins Sleep Scale. No serious adverse events occurred. This study presents preliminary results for subcutaneous continuous low-dose FMZ's effectiveness and safety in GAD. The findings suggest that it is a safe, well-tolerated, and feasible treatment option in this group of patients. Future randomised control trials are needed in this field to determine the efficacy of this treatment.

Ketamine Use for Management of Vaso-Occlusive Pain in Children with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) vaso-occlusive pain episode (VOE) management often includes non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, which can be inadequate and associated with significant side effects. Ketamine, a dissociative anesthetic, produces potent analgesic effects by blocking N-methyl-D-aspartate (NMDA) receptors, which impairs sensitization of spinal neurons to nociceptive stimuli. This mechanism allows ketamine to mitigate neuropathic pain and modulate opioid tolerance and opioid-induced hyperalgesias. Although only FDA-approved for use as an anesthetic agent, limited data suggest that low-dose ketamine is a safe and potentially effective adjunctive treatment for VOE pain. Objectives: This study aimed to characterize ketamine use for VOE management in children with SCD. Method: This retrospective cohort study summarizes a single-center experience regarding the use of ketamine for inpatient management of VOE in 156 admissions from 2014 to 2020 in which 44 unique children received ketamine. Results: Continuous low-dose ketamine infusion was most commonly prescribed to adolescents as an adjunct to opioids (median starting dose 2.0 mcg/kg/min; median maximum dose 3.0 mcg/kg/min). Ketamine was started a median of 13.7 hours after admission. Median ketamine infusion duration was 3 days (IQR 1.8-4.3). For admissions in which opioid was decreased during ketamine infusion, the median time from start of ketamine infusion to first opioid dose adjustment was 12.5 hours (IQR 3.25-36.6). In most encounters (n=119, 76.3%), ketamine infusion was discontinued prior to opioid PCA discontinuation. In 33 (21.2%) of encounters, the ketamine dose was decreased within 6 hours prior to discontinuation. The majority of encounters (79.3%) had a reduction in either PCA dose, continuous opioid infusion, or both while receiving ketamine. Low-dose ketamine infusion was well-tolerated overall, with side effects noted in 21.8% (n=34) of encounters. The most common side effects included dizziness (5.6%), hallucinations (5.1%), dissociation (2.6%), and sedation (1.9%). Nearly all side effects were reversible, resolving within 24 hours of dose reduction (n=11, 78.6%) or infusion discontinuation (n=21, 95.5%). There was no significant difference in patient sex or age at admission between groups with reported side effects compared to those without. There was a significant difference in hemoglobin genotype between groups (p=0.005). In both groups, most patients had hemoglobin SS. However, a higher percentage of encounters with side effects included patients with hemoglobin SC. Further, a higher percentage of patients in the no side effect group received hydroxyurea before admission (p=0.032) (Table 2). There were no reports of ketamine withdrawal. In 11 (7.1%) encounters, benzodiazepines were administered during ketamine infusion; 7 intravenously and 4 enterally. In most cases (n=5, 45.5%) the benzodiazepine was given for anxiety, in 2 cases (18.2%) for spasticity, 2 (18.2%) for spasm, 1 (9.1%) for agitation and 1 (9.1%) for pain. Benzodiazepines were administered within 12 hours after ketamine initiation in only 3 cases. Most patients who received ketamine went on to receive it again during a subsequent admission (72.1%, n=98). Conclusion: Ketamine infusion should be considered when developing individualized pain plans for children with SCD, and it may be particularly beneficial for those who have a history of inadequate pain relief from opioids or dose-limiting opioid side effects. The variability of ketamine administration highlights the need for standardized protocols for ketamine use in VOE management. Further prospective study is needed to establish the efficacy of ketamine infusion and to determine optimal dosing, which may be patient-specific. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Management of Generalised Anxiety Disorder with Low-Dose Continuous Infusions of Flumazenil: A Case Series

Generalised anxiety disorder (GAD) is a common anxiety disorder associated with social and occupational impairment. Recently, a theory was postulated that dysfunctional gamma aminobutyric acid type A receptors (GABAA) are implicated in anxiety symptomology, which could be corrected by flumazenil, an antagonist at the benzodiazepine binding site on the GABAA receptor. Participants had a primary diagnosis of GAD and were treated initially with an eight-day continuous low-dose flumazenil infusion (total 32 mg at a rate of 4 mg/24 h). Some participants were re-treated with a further four- or eight-day infusion. Treatment response was measured as a 50% reduction in anxiety or stress scores on the Depression Anxiety Stress Scale-21 (DASS-21). Remission was measured as scores ≤3 or ≤7 on the anxiety and stress subscales of the DASS-21, respectively. Eight cases are reported. All cases met the criteria for treatment response on the anxiety and stress subscale of the DASS-21. Remission was achieved in seven participants on the anxiety subscale and in five on the stress subscale. No changes in hepatic, renal, or haematological function were likely attributed to flumazenil. Data suggest that low-dose continuous flumazenil infusion manages GAD symptoms and is safe. Although these results are promising, future randomised control trials are required to confirm these results.

Is the Precipitation of Anxiety Symptoms Associated with Bolus Doses of Flumazenil a Barrier to Its Use at Low Continuous Doses in Benzodiazepine Withdrawal?

Introduction: Benzodiazepines (BZDs) are used in the management of anxiety and sleep disorders; however, chronic use is associated with tolerance and dependence. During withdrawal, symptoms of anxiety are often severe and problematic for patients and may lead to relapse or maintenance on low doses of BZDs. Low, continuous doses of flumazenil reduce BZD withdrawal symptoms in several studies; however, bolus doses are known to induce anxiety and precipitate panic. Accordingly, this study aimed to determine whether continuous low-dose flumazenil is anxiogenic like bolus doses. Method: In a randomised control cross over design, participants received a continuous low-dose flumazenil infusion for eight days at an approximate rate of 4 mg/24 h or placebo before crossing over to the alternate study arm. Participants were able to request diazepam as needed. The primary outcome was the change in state anxiety levels. Trait anxiety was also recorded at baseline and one month after the flumazenil/placebo infusion period. Results: BZD use was significantly reduced in both groups. There were no significant differences between state anxiety and the 95% confidence interval showed no evidence of a clinically significant anxiogenic effect from low-dose flumazenil. Trait anxiety was significantly reduced one month after the infusion period. Conclusion: There is no evidence that continuous low-dose flumazenil infusion significantly increases state anxiety levels to a clinically significant level. Interestingly, flumazenil may decrease state anxiety during BZD withdrawal, unlike bolus doses of flumazenil. Flumazenil may have an anxiolytic effect on trait anxiety, which was evident one month after treatment.

Continuous Intravenous Ketamine for Pain Control After Tibial or Femoral Osteotomy.

The purpose of this case series is to evaluate the potential of continuous intravenous ketamine administration as part of a multimodal strategy to reduce opioid requirements after high tibial osteotomy (HTO) and distal femoral osteotomy (DFO). We examined the average postoperative numerical rating scale pain intensity score from admission to the postanesthesia care unit to 8am of the first postoperative day of four patients who underwent HTO or DFO. Pain scores were analyzed as the time-weighted sum of pain intensity differences using the trapezoidal rule of the curve, resulting in an area under the curve (AUC). Patient A had an AUC of 2,828 over 1,180 minutes with an average pain score of 2.4/10. Patient B had an AUC of 1,418 over 1,285 minutes with an average pain score of 1.1/10. Patient C had an AUC of 4,217 over 1,155 minutes with an average pain score of 3.7/10. Patient D had an AUC of 4,498 over 1,030 minutes with an average pain score of 4.4/10. All were able to go home on postoperative day 1. This novel perioperative pain pathway including multiple non-opioid pain adjuncts and a low-dose continuous ketamine infusion is an effective method for pain management in knee periarticular osteotomies. Level 4; Case Series.

Comparison of Norepinephrine and Terlipressin vs Norepinephrine Alone for Management of Septic Shock: A Randomized Control Study.

PurposeTo compare norepinephrine and terlipressin vs norepinephrine alone for management of septic shock.Materials and methodsIn this prospective, randomized control trial, 50 adult patients with septic shock were randomized into two groups. Group I received a combination of injection terlipressin 0.02 µg/kg/min (fixed dose) infusion and injection norepinephrine 0.01 µg/kg/min infusion and group II received injection norepinephrine 0.01 µg/kg/min infusion alone. Dose of noradrenaline in both the groups was titrated to achieve the target MAP of 65–70 mm Hg. The data collected were the dose of norepinephrine required to maintain an MAP of above 65 mm Hg, urine output, serum lactate, procalcitonin level, C-reactive protein, sequential organ failure assessment (SOFA) score, total duration of vasopressor support, and incidences of the adverse effects.ResultsThe norepinephrine dose in group I vs group II at 12 hours was found to be 0.141 ± 0.067 vs 0.374 ± 0.096 µg/kg/min (p ≤0.005). The serum lactate was lower, and urine output was higher in group I than group II (p <0.05). Group I had a significantly greater reduction in SOFA score in 12 hours than group II. Group I patient also had a significant decrease in the duration of vasopressor administration than group II patients being discharged from the ICU. However, there was no difference in the mortality between the two groups during their ICU stay.ConclusionA low-dose continuous infusion of terlipressin and norepinephrine could help attain early resuscitation goals for managing patients with septic shock.How to cite this articleSahoo P, Kothari N, Goyal S, Sharma A, Bhatia PK. Comparison of Norepinephrine and Terlipressin vs Norepinephrine Alone for Management of Septic Shock: A Randomized Control Study. Indian J Crit Care Med 2022;26(6):669–675.

Abstract No.: ABS0369: Comparison of norepinephrine and terlipressin versus norepinephrine alone for management of septic shock: A randomised control study.

Background and Aims:Terlipressin, a V1 receptor-selective analogue of vasopressin, can produce potent vasoconstriction of blood vessels and can reduce the dose of norepinephrine required for maintaining the mean arterial pressure (MAP) and organ perfusion in septic shock, thus avoiding its side effects.Methods:In this prospective, randomised control trial, 50 adult patients with septic shock were divided into two groups. Group 1 received a combination of terlipressin 0.02 µg/kg/min (fixed dose) infusion and noradrenaline 0.01–3.0 µg/kg/min infusion intravenously. Group 2 received intravenous noradrenaline 0.01–3.0 µg/kg/min infusion alone. Noradrenaline in both groups was targeted to achieve an MAP of 65–70 mm of Hg. The data collected were the dose of noradrenaline required to maintain an MAP of above 65 mm of Hg, urine output, serum lactate, procalcitonin level, C-Reactive protein, sequential organ failure assessment score (SOFA) score, total duration of the vasopressor support, and incidence of adverse effects.Results:The noradrenaline dose in group 1 versus group 2 at 12 hours was found to be 0.141 ± 0.067 vs 0.374 ± 0.096 µg/kg/min (p=<0.005). The blood lactate concentration was significantly lower, and the urine output was higher in group 1 than in group 2 (p=<0.005). Group 1 had a significantly greater reduction in SOFA score in 12 hours than group 2. However, there was no difference in the mortality between the two groups during their intensive care unit stay.Conclusion:A low-dose continuous infusion of terlipressin along with norepinephrine could help attain better organ perfusion and early resuscitation goals for management of patients with septic shock without causing the side effects related to catecholamines.

Penehyclidine for prevention of postoperative nausea and vomiting following bimaxillary orthognathic surgery: a randomized, double-blind, controlled trial

PurposeTo investigate the efficacy and safety of low-dose bolus plus continuous infusion of penehyclidine in preventing postoperative nausea and vomiting (PONV) following bimaxillary surgery.MethodsThree hundred fifty-four patients were randomly allocated into three groups. In the Control group, placebo (normal saline) was injected before anesthesia and infused over 48 h after surgery; in the Bolus group, 0.5 mg penehyclidine was injected before anesthesia, whereas placebo was infused after surgery; in the Infusion group, 0.25 mg penehyclidine were injected before anesthesia, another 0.25 mg penehyclidine was infused after surgery. The primary endpoint was the incidence of PONV within 72 h.ResultsA total of 353 patients were included in intention-to-treat analysis. The PONV incidence was 61.0% (72/118) in the Control group, 40.2% (47/117) in the Bolus group, and 28.0% (33/118) in the Infusion group. The incidence was significantly lower in the Bolus group than in the Control group (RR 0.66; 95% CI 0.51–0.86; adjusted P = 0.003) and in the Infusion group than in the Control group (RR 0.46; 95% CI 0.33–0.63; adjusted P < 0.001); the difference between the Infusion and Bolus groups was not statistically significant (RR 0.70; 95% CI 0.48–1.00; adjusted P = 0.144). Emergence agitation occurred more frequently in the Bolus group than in the Control group (36.8% [43/117] vs. 21.2% [25/118], adjusted P = 0.027), but did not differ significantly between the Infusion and Control groups.ConclusionsA low-dose bolus plus continuous infusion of penehyclidine was effective in preventing PONV without increasing emergence agitation.Trial registrationClinicaltrials.gov. Identifier: NCT04454866.

Heparin Infusion for Central Line Patency and Corrected Gestational Age May Affect Coagulation Studies in the Neonatal Intensive Care Unit

Introduction: Addition of heparin (i.e., 0.5-1 U/mL) to maintenance intravenous (IV) fluids in the neonatal intensive care unit (NICU) is frequently done to reduce the risk of thrombus-related catheter dysfunction. Since heparin could affect coagulation testing, we sought to determine whether coagulation study results are significantly affected by the presence of heparin in IV fluids.Methods: Chart review was performed on all patients in the NICU that had either prothrombin time (PT) or partial thromboplastin time (aPTT) drawn during their NICU course. Only the first instance of coagulation studies drawn on each patient was considered. Patients were excluded if they had a medical condition (e.g., sepsis) which could potentially affect coagulation studies or if they received blood products. Coagulation study results and whether or not the patient was receiving heparin in IV fluids for vascular access patency were extracted in addition to other demographic information, including corrected gestational age (CGA). In our institution, all NICU patients with a central line where the flow rate in any lumen is less than 5 mL/hr receive heparin. Comparative analyses between the group receiving heparin in IV fluids and the group not receiving heparin were performed. Wilcoxon rank sum test was used to detect differences in distribution between groups and adjustment was performed by fitting one multiple linear regression model to medians and a separate multiple linear regression model to standard deviations; Z-scores were calculated based off these two models.Results: One hundred and forty four patients (mean age 17.9 days, 50% male) were included in the analysis. Initial unadjusted analysis revealed that patients who received heparin in IV fluids for vascular access patency (n=77, 53.5%) had prolongation of PT and aPTT compared to patients who did not receive heparin (n=67, 46.5%) in IV fluids for vascular access patency (means 16.2 seconds vs. 13.5 seconds [p=8 x 10-7] and 62.9 vs. 43.9 seconds [p=9 x 10-8], for PT and aPTT, respectively). No significant sex-based difference was noted.In 132 patients with accurate CGA data available, mean CGA was lower in the heparin group (n=75) at 36.5 weeks compared to the no heparin group (n=57) at 41.6 weeks (p<0.0001). When results were adjusted for CGA, the difference remained significant but much less so (z-score mean difference 0.52 [p=0.01] and 0.48 [p=0.003], for PT and aPTT, respectively).Conclusion: Coagulation study parameters appear to be prolonged in patients receiving heparin for vascular access patency compared to those who are not; however, much of this difference is accounted for by corrected gestational age. Proper specimen collection (i.e., sufficient draw-back prior to collecting the sample) for accurate interpretation of results in these patients is recommended. In addition, laboratories should consider taking corrected gestational age and continuous low-dose heparin infusion into account when establishing reference ranges for coagulation studies. DisclosuresNo relevant conflicts of interest to declare.

Postoperative Low-Dose Tranexamic Acid After Major Spine Surgery: A Matched Cohort Analysis.

ObjectiveThis was a retrospective, cohort study investigating the efficacy and safety of continuous low-dose postoperative tranexamic acid (PTXA) on drain output and transfusion requirements following adult spinal deformity surgery. MethodsOne hundred forty-seven patients undergoing posterior instrumented thoracolumbar fusion of ≥ 3 vertebral levels at a single institution who received low-dose PTXA infusion (0.5–1 mg/kg/hr) for 24 hours were compared to 292 control patients who did not receive PTXA. The cohorts were propensity matched based on age, sex, American Society of Anesthesiologist physical status classification, body mass index, number of surgical levels, revision surgery, operative duration, and total intraoperative TXA dose (n = 106 in each group). Primary outcome was 72-hour postoperative drain output. Secondary outcomes were number of allogeneic blood transfusions. ResultsThere was no significant difference in postoperative drain output in the PTXA group compared to control (660 ±420 mL vs. 710 ±490 mL, p = 0.46). The PTXA group received significantly more crystalloid (6,100 ±3,100 mL vs. 4,600 ±2,400 mL, p < 0.001) and red blood cell transfusions postoperatively (median [interquartile range]: 1 [0–2] units vs. 0 [0–1] units; incidence rate ratio [95% confidence interval], 1.6 [1.2–2.2]; p = 0.001). Rates of adverse events were comparable between groups. ConclusionContinuous low-dose PTXA infusion was not associated with reduced drain output after spinal deformity surgery. No difference in thromboembolic incidence was observed. A prospective dose escalation study is warranted to investigate the efficacy of higher dose PTXA.

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.

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.

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.

Adjunct low-dose ketamine infusion vs standard of care in mechanically ventilated critically ill patients at a Tertiary Saudi Hospital (ATTAINMENT Trial): study protocol for a randomized, prospective, pilot, feasibility trial

BackgroundA noticeable interest in ketamine infusion for sedation management has developed among critical care physicians for critically ill patients. The 2018 Pain, Agitation/sedation, Delirium, Immobility, and Sleep disruption guideline suggested low-dose ketamine infusion as an adjunct to opioid therapy to reduce opioid requirements in post-surgical patients in the intensive care unit (ICU). This was, however, rated as conditional due to the very low quality of evidence. Ketamine has favorable characteristics, making it an especially viable alternative for patients with respiratory and hemodynamic instability. The Analgo-sedative adjuncT keTAmine Infusion iN Mechanically vENTilated ICU patients (ATTAINMENT) trial aims to assess the effect and safety of adjunct low-dose continuous infusion of ketamine as an analgo-sedative compared to standard of care in critically ill patients on mechanical ventilation (MV) for ≥ 24 h.Methods/designThis trial is a prospective, randomized, active controlled, open-label, pilot, feasibility study of adult ICU patients (> 14 years old) on MV. The study will take place in the adult ICUs in the King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh, Saudi Arabia, and will enroll 80 patients. Patients will be randomized post-intubation into two groups: the intervention group will receive an adjunct low-dose continuous infusion of ketamine plus standard of care. Ketamine will be administered over a period of 48 h at a fixed infusion rate of 2 μg/kg/min (0.12 mg/kg/h) in the first 24 h followed by 1 μg/kg/min (0.06 mg/kg/h) in the second 24 h. The control group will receive standard of care in the ICU (propofol and/or fentanyl and/or midazolam) according to the KFSH&RC sedation and analgesia protocol as clinically appropriate. The primary outcome is MV duration until ICU discharge, death, extubation, or 28 days post-randomization, whichever comes first.DiscussionThe first patient was enrolled on 1 September 2019. As of 10 October 2019, a total of 16 patients had been enrolled. We expect to complete the recruitment by 31 December 2020. The findings of this pilot trial will likely justify further investigation for the role of adjunct low-dose ketamine infusion as an analgo-sedative agent in a larger, multicenter, randomized controlled trial.Trial registrationClinicalTrials.gov: NCT04075006. Registered on 30 August 2019. Current controlled trials: ISRCTN14730035. Registered on 3 February 2020.