Doses Of Norepinephrine Research Articles

The impact of norepinephrine dose reporting heterogeneity on mortality prediction in septic shock patients

BackgroundNorepinephrine (NE) is a cornerstone drug in the management of septic shock, with its dose being used clinically as a marker of disease severity and as mortality predictor. However, variations in NE dose reporting either as salt formulations or base molecule may lead to misinterpretation of mortality risks and hinder the process of care.MethodsWe conducted a retrospective analysis of the MIMIC-IV database to assess the impact of NE dose reporting heterogeneity on mortality prediction in a cohort of septic shock patients. NE doses were converted from the base molecule to equivalent salt doses, and their ability to predict 28-day mortality at common severity dose cut-offs was compared.Results4086 eligible patients with septic shock were identified, with a median age of 68 [57–78] years, an admission SOFA score of 7 [6–10], and lactate at diagnosis of 3.2 [2.4–5.1] mmol/L. Median peak NE dose at day 1 was 0.24 [0.12–0.42] μg/kg/min, with a 28-day mortality of 39.3%. The NE dose showed significant heterogeneity in mortality prediction depending on which formulation was reported, with doses reported as bitartrate and tartrate presenting 65 (95% CI 79–43)% and 67 (95% CI 80–47)% lower ORs than base molecule, respectively. This divergence in prediction widened at increasing NE doses. When using a 1 μg/kg/min threshold, predicted mortality was 54 (95% CI 52–56)% and 83 (95% CI 80–87)% for tartrate formulation and base molecule, respectively.ConclusionsHeterogeneous reporting of NE doses significantly affects mortality prediction in septic shock. Standardizing NE dose reporting as base molecule could enhance risk stratification and improve processes of care. These findings underscore the importance of consistent NE dose reporting practices in critical care settings.

Comparative Efficacy of Intermittent Bolus Doses of Phenylephrine and Norepinephrine in Preventing Maternal Bradycardia during Cesarean Section under Spinal Anesthesia: A Randomized Controlled Trial

Background and Aims: Maternal hypotension is a common concern during cesarean sections (CS) with spinal anesthesia and can have adverse consequences for both the mother and fetus. This study aimed to investigate the prophylactic effectiveness of intermittent boluses of phenylephrine and norepinephrine in preventing maternal bradycardia during maintenance of systolic blood pressure (SBP) within 90–100% of baseline. Material and Methods: Two hundred American Society of Anesthesiologists physical status -II parturients scheduled for CS with subarachnoid block (SAB) were randomly assigned to Group A (phenylephrine, 50 µg) or Group B (norepinephrine, 4 µg). The primary goal was to assess the incidence of maternal bradycardia (≤50 bpm) whilst SBP maintenance at 90-100% of baseline. The secondary objectives encompassed total boluses administered, episodes of hypertension (≥120% of baseline), Intraoperative nausea and vomiting (IONV), and neonatal APGAR scores. The time from intrathecal injection to fetal delivery (induction–delivery interval) was also evaluated. Results: Both norepinephrine and phenylephrine groups effectively prevented spinal-induced hypotension, with similar outcomes However, Group A (phenylephrine) experienced a significantly higher incidence of bradycardia (18%) compared to Group B (norepinephrine) with only 5% (P=0.016). Episodes of hypertension, IONV, and neonatal APGAR scores were comparable between the two groups. Conclusion: Intermittent boluses of norepinephrine and phenylephrine demonstrated equivalent efficacy in preventing spinal-induced hypotension during CS. However, norepinephrine exhibited an advantage over phenylephrine by significantly reducing the incidence of bradycardia. These findings support the consideration of norepinephrine as an effective alternative vasopressor for maintaining maternal hemodynamics during CS under SAB.

Internal Jugular Vein Collapsibility Index versus Inferior Vena Cava Collapsibility Index Guided Preloading for Prevention of Spinal Anesthesia Induced Hypotension During LSCS: An Interventional Study

Background and Aims: Goal directed fluid therapy (GDFT) in parturients helps to prevent spinal anesthesia induced hypotension (SAIH) and volume overload. This interventional study compared the inferior vena cava collapsibility index (IVCCI) and the internal jugular vein collapsibility index (IJVCI) guided preloading for prevention of SAIH during lower segment ceserean section (LSCS) in terms of the incidence of SAIH as the primary outcome and the total amount of fluid, mean dose of the vasopressor, the number of boluses of vasopressor required, and the incidence of intra-operative complications as secondary outcomes. Methodology: A total of 144 full-term parturients aged 20–40 years with American society of anaesthesiologists (ASA) grade II, height (140–165 cms), weight (40–70 kgs), those who were fluid responders, and those who had a window period of 1 hour before surgery under spinal anesthesia (SA) undergoing LSCS were allocated into two groups (n = 72): group IJV and group IVC. Ultrasonography (USG) guided Internal jugular vein (IJV) and Inferior vena cava (IVC) collapsibility index (CI) was recorded an hour before spinal anesthesia (SA) as per the groups assigned and preloaded accordingly. After SA, the incidence of SAIH, the requirement of vasopressor, and fluid were recorded, and side effects were managed. Results: In group IVC, the incidence of SAIH (36.84%), mean dose (3.51 ± 5.02 µg), and mean boluses (0.44 ± 0.63) of norepinephrine required to manage hypotension were significantly lower than in group IJV, and the mean goal directed fluid administered before LSCS (504.46 ± 181.48 ml) and overall mean total fluid (1104.39 ± 160.99 ml) administered were significantly higher than in group IJV. Except for shivering, the incidence of all other complications was significantly lower in group IVC (p < 0.05). Conclusion: Both IVCCI and IJVCI guided preloading are effective in combating SAIH during LSCS, but IVCCI is comparatively better than IJVCI for CI guided preloading.

Association between maximum norepinephrine dosage and mortality risk in neonates with septic shock

The high-dose usage of norepinephrine is thought to cause high mortality in patients with septic shock. This study aims to explores the correlation between the maximum norepinephrine (NE) dosage (MND) and mortality in neonates with septic shock. This retrospective cohort study included neonates with evidence of septic shock and those who received NE infusion. The study included 123 neonates, with 106 in the survival group and 17 in the death group. The death group exhibited significantly lower birth weight (p = 0.022), 1-min Apgar score (p = 0.005), serum albumin (p < 0.001), and base excess (BE) (p = 0.001) levels, but higher lactate (LAC) levels (p = 0.009) compared to the survival group. MND demonstrated an ROC area under the curve of 0.775 (95% CI 0.63–0.92, p < 0.001) for predicting mortality, with an optimal threshold of 0.3 µg/(kg·min), a sensitivity of 82.4%, and a specificity of 75.5%. Multivariate logistic regression indicated that an MND > 0.3 µg/(kg·min) (OR, 12.08, 95% CI 2.28–64.01) was associated with a significantly higher mortality risk. Spearman rank correlation showed a positive correlation between MND and LAC (r = 0.252, p = 0.005), vasoactive-inotropic score (VIS) (r = 0.836, p < 0.001), and a negative correlation with BE (r = − 0.311, p = 0.001). MND > 0.3 µg/(kg min) is a useful predictive marker of mortality in neonatal septic shock.

Norepinephrine or phenylephrine for the prevention of post-spinal hypotension after caesarean section: A double-blinded, randomized, controlled study of fetal heart rate and fetal cardiac output

Study objectiveSpinal anesthesia often causes hypotension, with consequent risk to the fetus. The use of vasopressor agents has been highly recommended for the prevention of spinal anesthesia-induced hypotension during caesarean delivery. Many studies have shown that norepinephrine can provide more stable maternal hemodynamics than phenylephrine. We therefore tested the hypothesis that norepinephrine preserves fetal circulation better than phenylephrine when used to treat maternal hypotension consequent to spinal anesthesia. DesignProspective, randomized, double-blinded study. SettingOperating room. PatientsWe recruited 223 parturients with uncomplicated singleton pregnancies who were scheduled for elective caesarean section under combined spinal-epidural anesthesia. InterventionsThe patients received prophylactic intravenous infusion of either 0.08 μg/kg/min norepinephrine or 0.5 μg/kg/min phenylephrine for prevention of spinal anesthesia-induced hypotension. MeasurementsChanges in fetal heart rate and fetal cardiac output before and after spinal anesthesia were measured using noninvasive Doppler ultrasound. Main results90 subjects who received norepinephrine infusion and 93 subjects who received phenylephrine infusion were ultimately analyzed in the present study. The effects of norepinephrine and phenylephrine on the change of fetal heart rate and fetal cardiac output at 3 and 6 min after spinal block were similar. Although there was a statistically significant decrease in fetal cardiac output at 6 min after subarachnoid block initiation in both the norepinephrine group (mean difference 0.02 L/min; 95% CI, 0–0.04 L/min; P = 0.03) and the phenylephrine group (mean difference 0.02 L/min; 95% CI, 0–0.04 L/min; P = 0.02), it remained within the normal range. ConclusionsProphylactic infusion of comparable doses of phenylephrine or norepinephrine has similar effects on fetal heart rate and cardiac output changes after spinal anesthesia. Neither phenylephrine nor norepinephrine has meaningful detrimental effects on fetal circulation or neonatal outcomes.

ANGIOTENSIN II IN THE TREATMENT OF DISTRIBUTIVE SHOCK: A SYSTEMATIC-REVIEW AND META-ANALYSIS.

Objective: While nonnorepinephrine vasopressors are increasingly used as a rescue therapy in cases of norepinephrine-refractory shock, data on their efficacy are limited. This systematic review and meta-analysis aims to synthesize existing literature on the efficacy of angiotensin II (ATII) in distributive shock. Methods: We preregistered our meta-analysis with PROSPERO (CRD42023456136). We searched PubMed, Scopus, and gray literature for studies presenting outcomes on ATII use in distributive shock. The primary outcome of the meta-analysis was all-cause mortality. We used a random effects model to calculate pooled risk ratio (RR) and 95% confidence intervals (CIs). Results: By incorporating data from 1,555 patients included in 10 studies, we found that however, all-cause mortality was similar among patients receiving ATII and controls (RR = 1.02; 95% CI: 0.89 to 1.16, P = 0.81), the reduction in norepinephrine or norepinephrine-equivalent dose at 3 h after treatment initiation was greater among patients receiving ATII (MD = -0.06; 95% CI: -0.11 to -0.02, P = 0.008), while there were no higher rates of adverse events reported among ATII patients. Conclusions: While ATII did not reduce mortality among distributive shock patients, it allowed for significant adjunctive vasopressor reduction at 3 h without an increase in reported adverse events, deeming it a viable alternative for the increasingly adopted multimodal vasopressor for minimizing catecholamine exposure and its adverse events.

Comparison of "Huaxi-1" or "histidine-tryptophan-ketoglutarate" cardioplegia in an animal model.

Using a pig model of cardiopulmonary bypass, we compared outcomes after cardioplegia either with our in-house "Huaxi-1" solution containing natural blood and crystalloid or with the entirely crystalloid, commercially available "histidine-tryptophan-ketoglutarate" solution. Cardiopulmonary bypass was established in 12 healthy male pigs, who were randomized to receive a single dose of either Huaxi-1 or entirely crystalloid. All animals were then subjected to whole-heart ischemia for 90 min, followed by 2 h of reperfusion, after which myocardial injury was assessed in terms of cardiac function, myocardial pathology and levels of biomarkers in plasma, while levels of high-energy phosphate in myocardium were assayed using liquid chromatography. Animals given Huaxi-1 cardioplegia required significantly less time to be weaned off bypass, they received significantly lower doses of norepinephrine, and they showed significantly higher levels (mean ± SD) of adenosine triphosphate (14 ± 4 vs. 8 ± 2 µg/mg, P = 0.005), adenosine diphosphate (16 ± 2 vs. 13 ± 2 µg/mg, P = 0.046), and total adenine nucleotide (37 ± 4 vs. 30 ± 3 µg/mg, P = 0.006) in myocardium after 2 h of reperfusion. They also showed less severe bleeding, edema and injury to mitochondria and myofibers in myocardium. The two groups did not differ significantly in doses of inotropic drugs received, cardiac output or levels of biomarkers in plasma. In this animal model of healthy hearts subjected to 90 min of ischemia, Huaxi-1 cardioplegia may be superior to entirely crystalloid cardioplegia for promoting energy generation and attenuating ischemia/reperfusion injury in myocardium.

Effects of intravenous inflammasome inhibitor (NuSepin) on suppression of proinflammatory cytokines release induced by cardiopulmonary bypass in swine model: a pilot study

The systemic inflammatory response syndrome can occur due to an inflammatory reaction to the release of cytokines, and it has been linked to the circulation of pro- and anti-inflammatory cytokines. The cardiopulmonary bypass (CPB) system is known to activate numerous inflammatory pathways. Applying CPB in large animals for an extended period may be useful as a controlled experimental model for systemic inflammatory responses. The authors hypothesized that 0.2 mg/kg NuSepin® would inhibit CBP-induced proinflammatory cytokine release, and attenuate CPB-induced vasoplegia. CPB was maintained for 2 h in 8 male Yorkshire pigs. Ten ml of saline was administered intravenously to the control group, while the study group received 10 ml of NuSepin® (0.2 mg/kg), before start of CPB. Blood samples were collected at four different time points to evaluating the level of cytokine (TNF-α, IL-1β, IL-6, IL-8) release during and after CBP. All vital signals were recorded as continuous waveforms using the vital recorder®. Our study demonstrated that IL-6 increased in both groups during CPB remained unchanged. However, in the Nusepin group, IL-6 levels rapidly decreased when CPB was stopped and the proinflammatory reaction subsided. Furthermore, the dose of norepinephrine required to maintain a mean pressure of 60 mmHg was also lower in the Nusepin group.

Dose-Response Study of Norepinephrine Infusion for Maternal Hypotension in Preeclamptic Patients Undergoing Cesarean Delivery Under Spinal Anesthesia.

Spinal anesthesia remains the preferred mode of anesthesia for preeclamptic patients during cesarean delivery. We investigated the incidence of maternal hypotension under spinal anesthesia during cesarean delivery, by comparing different prophylactic infusion rates of norepinephrine with normal saline. We randomly allocated 180 preeclamptic patients (45 in each groups) aged 18-45 scheduled for cesarean delivery to receive one of four prophylactic norepinephrine infusions at doses of 0 (normal saline group), 0.025 (0.025 group), 0.05 (0.05 group), or 0.075 (0.075 group) µg/kg/min following spinal anesthesia. The primary endpoint was the incidence of maternal hypotension (systolic blood pressure < 80% of baseline). The incidence of maternal hypotension was reduced with different prophylactic infusion rates of norepinephrine (26.7%, 15.6%, and 6.7%) compared with normal saline (37.8%) with a significant decreasing trend (p = 0.002). As the infusion doses of norepinephrine increased, there is a significant decreasing trend in deviation of systolic blood pressure control (median performance error; median absolute performance error) from baseline (p < 0.001; p < 0.001) and need for rescue norepinephrine boluses (p = 0.020). The effective dose 50 and effective dose 90 of prophylactic norepinephrine infusion were - 0.018 (95% confidence interval - 0.074, 0.002) µg/kg/min and 0.065 (95% confidence interval 0.048, 0.108) µg/kg/min, respectively. Prophylactic infusion of norepinephrine, as compared to no preventive measures, can effectively reduce the incidence of maternal hypotension in preeclamptic patients under spinal anesthesia during cesarean delivery, without increasing other adverse events for either the mother or neonate. Clinical trials.gov identifier number NCT04556370.

Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial

Background Fluid resuscitation is an essential component for sepsis treatment. Although several studies demonstrated that dynamic variables were more accurate than static variables for prediction of fluid responsiveness, fluid resuscitation guidance by dynamic variables is not standard for treatment. The objectives were to determine the effects of dynamic inferior vena cava (IVC)-guided versus (vs.) static central venous pressure (CVP)-guided fluid resuscitation in septic patients on mortality; and others, i.e., resuscitation targets, shock duration, fluid and vasopressor amount, invasive respiratory support, length of stay and adverse events. Methods A single-blind randomized controlled trial was conducted at Thammasat University Hospital between August 2016 and April 2020. Septic patients were stratified by acute physiologic and chronic health evaluation II (APACHE II) &lt;25 or ≥25 and randomized by blocks of 2 and 4 to fluid resuscitation guidance by dynamic IVC or static CVP. Results Of 124 patients enrolled, 62 were randomized to each group, and one of each was excluded from mortality analysis. Baseline characteristics were comparable. The 30-day mortality rates between dynamic IVC vs. static CVP groups were not different (34.4% vs. 45.9%, p=0.196). Relative risk for 30-day mortality of dynamic IVC group was 0.8 (95%CI=0.5-1.2, p=0.201). Different outcomes were median (interquartile range) of shock duration (0.8 (0.4-1.6) vs. 1.5 (1.1-3.1) days, p=0.001) and norepinephrine (NE) dose (6.8 (3.9–17.8) vs. 16.1 (7.6–53.6) milligrams, p=0.008 and 0.1 (0.1-0.3) vs. 0.3 (0.1-0.8) milligram⋅kilogram−1, p=0.017). Others were not different. Conclusions Dynamic IVC-guided fluid resuscitation does not affect mortality of septic patients. However, this may reduce shock duration and NE dose, compared with static CVP guidance.

Acute-on-chronic heart failure leading to cardiogenic shock: any role for intra-aortic balloon pump? Results from a multicenter retrospective data collection

Abstract Funding Acknowledgements None. Background Intra-aortic balloon pump (IABP) implantation has been significantly reduced since IABP-SHOCK II trial did not show any clinical benefit in acute myocardial infarction (AMI)-related cardiogenic shock (CS)(1). For a long time, AMI has been recognized as the first cause of CS; however, in the last years, acute-on-chronic heart failure (HF)-CS has become predominant. We hypothesized that in HF-CS population the IABP may decrease mortality having a role in decreasing left ventricular afterload and improving peripheral perfusion(2). Purpose To investigate whether, in this phenotypical category of cardiogenic shock, IABP could improve 28-days mortality. Methods Multicenter retrospective observational study including adult HF-CS patients admitted in cardiac or general intensive care units in 3rd level centers. Hemodynamic variables before (T0) and after IABP implantation (T1), pharmacological support and outcome data were collected. Independent samples t-test was applied to assess any difference between IABP and non-IABP group; Kaplan-Meier and Cox’s regression (forward stepwise method) were performed as survival analysis on 28-days mortality. Results 160 patients (35.6% female, 61 [47-74] years-old) were included from three centers; overall mortality was 42.5%. 50% received IABP support; amongst IABP patients, 24 received further MCS with VA-ECMO (p &amp;lt;0.001) and 4 with Impella (p 0.120). Patients’ baseline characteristics are shown in Figure 1-A. IABP patients had lower 28-days mortality. Patients who received IABP were younger, had lower systolic blood pressure (SBP), pulse pressure (PP) and lactate levels at T0. In reference to catecholaminergic drugs, patients supported with IABP had lower norepinephrine doses and vasoactive inotropic score (VIS) at baseline. After IABP implantation, no significant difference between the two groups in the time variation of these parameters was observed (Figure 1-B). Survival analysis graphs are shown in Figure 2. At Cox’s regression, a significant effect on 28-days mortality was found for IABP (HR 0.510 [0.293-0.887], p 0.017), SCAI classification-stage D (HR 2.582 [1.315-5.072], p 0.006), VIS-T0 above 15 (HR 2.348 [1.407-3.921], p 0.001) and SBP-T0 above 95 mmHg (HR 1.361 [1.016-1.823], p 0.039); no significant association was found for age above 61 years (overall median value) (p 0.091), mechanical ventilation (p 0.367), PP-T0 (0 0.081) and lactate-T0 (p 0.227). Conclusions Considering the specific pathophysiology of HF-CS, IABP may have a role in reducing mortality. These retrospective data need to be validated and compared with those deriving from ongoing randomized controlled trials(3).

Role of invasive hemodynamics monitoring in sepsis intensive care

The objective was to study the effect of early planned use of transpulmonary thermodilution (TPTD) and therapeutic measures to stabilize blood circulation on the clinical outcome of sepsis.Materials and methods. The cohort study involved 132 patients with abdominal sepsis with SOFA &gt;7 and blood lactate &gt;1.6 mmol/L. Septic shock was diagnosed in 56 % of patients. TPTD in the early periods of intensive care was began in 53.8 % of patients. Logistic regression and ROC-analysis were used to process the data.Results. Early use of invasive monitoring (OR 2,3715, 95 % CI 1,1107–5,0635, p=0,026, AUC 0.655) and infusion volume &gt;43 ml/kg per day (OR 1.0313, 95 % CI 1.0073–1.0558, p=0.01, AUC 0.677) were predictors of survival in patients with abdominal sepsis. The use of TPTD compared to patients of group II was accompanied by an increase in the daily infusion volume (53.7 [38.1–63.5] vs 38.2 [29.9–47.2], ml/kg per day, p = 0.0001), more frequent use of inotropic drugs (39.4 vs 16.4 %, p = 0.004), and higher level of the inotropic scale (0 [0–4.7] vs 0 [0–0], p = 0.01). There were no differences in the frequency of prescription (57.7 vs 65.5 %, p = 0.376) and dosages (0.2 [0.1–0.4] vs 0.3 [0.2–0.4] μg/kg/min, p = 0.554) of norepinephrine. Twenty-eight-day mortality in groups I and II was 31 and 50.8 % (p = 0.022), hospital mortality was 32.9 and 54.0 % (p = 0.014).Conclusion. When assessed by SOFA &gt; 7 points and lactatemia &gt; 1.6 mmol/L, the onset of TPTD and infusion volume &gt; 43 mL/kg/day increase the likelihood of survival of patients with abdominal sepsis, as a result, 28-day and hospital mortality decrease by 1.6 times. The use of invasive monitoring of central hemodynamics in this clinical situation is accompanied by an increase in the prescription of inotropes by 2.4 times with an unchanged intensity of norepinephrine use.

Mesenteric Ischemia after Cardiac Surgery.

Mesenteric ischemia (Me-Is) after cardiac surgery is underreported in present literature but has still earned the bad reputation of a dismal prognosis. This study adds clinical outcomes in a large patient cohort. Between 2009 and 2019 of the 22,590 patients undergoing cardiac surgery at our facility 106 (0.47%) developed Me-Is postoperatively. Retrospective patient data was analyzed. Additionally, patients were stratified by outcome-survivors and nonsurvivors. Patients were predominantly male (n = 68, 64.2%), mean age was 71.2 ± 9.3 years. Most procedures were elective (n = 85, 80.2%) and comprised of more complex combined procedures (50.9%) and redos (17.9%). Mean EuroSCORE II averaged 10.9 ± 12.2%. Survival at 30 days was 49.1% (n = 52). Clinical baseline and procedural characteristics did not differ significantly between survivors and nonsurvivors. The median postoperative interval until symptom onset was 5 days in both groups. Survivors were more frequently diagnosed by computed tomography and nonsurvivors based on clinical symptoms. Me-Is was predominantly nonocclusive (n = 84, 79.2%). Laparotomy was the main treatment in both groups (n = 45, 78.8% vs. n = 48, 88.9%, p = 0.94). Predictors of mortality were maximum norepinephrine doses (hazard ratio [HR] 8.29, confidence interval [CI] 3.39-20.26, p < 0.0001), lactate levels (HR 1.06, CI 1.03-1.09), and usage of inotropes (HR 2.46, CI 1.41-4.30). The prognosis of Me-Is following cardiac surgery is poor-independently from diagnostic or treatment patterns. There exists a significant asymptomatic time period postoperatively, in which pathophysiologic processes seem to cross the Rubicon. After clinical demarcation, the further course can almost no longer be influenced.

Norepinephrine Salt Formulations and Risk of Therapeutic Error: Results of a National Survey

Norepinephrine is available commercially in solution containing its salt (eg, tartrate), but only the base form (ie, norepinephrine base) is active pharmacologically. Unfortunately, the outer label of drug packages frequently reports the dosage of norepinephrine as a salt, which can lead potentially to therapeutic errors when prescribing norepinephrine. We performed a survey to assess the level of awareness of this issue. National survey. Acute care units of Italian hospitals. Acute care physicians and nurses. A 15-item online survey was emailed to 305 critical care practitioners in Italy. Questions included information on the participants' background, methods of diluting norepinephrine, interpretation of recommended doses from guidelines, and a sample case related to the preparation and administration of the drug. We collected 106 responses from 54 hospitals. All hospitals used norepinephrine bitartrate salt. Of the participants, 53% responded that the guidelines express norepinephrine dosages as a salt, 23% as the base form, and 24% were unsure or unaware about it. The simulated patient-dose calculation was resolved in 81% of cases with an incorrect calculation referring to the norepinephrine salt and only in 19% referring to the norepinephrine base. There is significant variability in dosage management of norepinephrine across different hospital units, as well as a lack of knowledge regarding the salt-to-base ratio. Scientific publications (eg, guidelines) should specify whether they are referring to the base or salt form of norepinephrine. The adoption of different labeling and national standards for dilution may decrease the risk of therapeutic errors.

Effects of aging on vasoconstrictor responses of diaphragm arterioles

Introduction: In health, the diaphragm is the most important inspiratory muscle and the only skeletal muscle that is continuously recruited throughout life. Because of the diaphragm’s importance to generating the exercise hyperpnea and wealth of evidence that diaphragm fatigue and exhaustion can impair exercise tolerance, we were interested in whether the exercise intolerance that attends older populations might be associated with altered diaphragm vasomotor control. While it is known that aging compromises peripheral skeletal muscle vasomotor control, it is not known if similar impairments are present in the respiratory muscle vasculature, namely the diaphragm. Therefore, we tested the hypothesis that advanced age decreases diaphragm arteriole contractile responses to alpha-adrenergic agonists. Methods: 4–5 month old Fischer rats and 22–24 month old Fischer rats were divided by age into two groups: young (Y) and old (O). In Y and O, diaphragm first order (1A) arterioles (~200μm diameter, ~2μm in length) were isolated, cannulated, and pressurized to develop spontaneous tone. Following this, contractile responses to cumulative doses of norepinephrine (NE) and phenylephrine (PE) (10−9 to 10−4M) were determined. Results and Conclusion: The physical characteristics of the two groups differed as O were heavier than Y. However, with respect to the diaphragm 1A arterioles, there were no differences in spontaneous tone development (%) or maximal diameter (μm) between Y (38 ± 4%; 132 ± 19μm) and O (37 ± 4%; 157 ± 14 μm; both P &gt;0.05). In diaphragm 1A arterioles, the maximal vasoconstrictor response to NE was also not different between O and Y animals (O: 37 ± 8% vs. Y: 45 ± 1%; p &gt; 0.05). However, the maximal vasoconstrictor response to PE was greater in Y compared to O (O: 29 ± 3% vs. Y: 39 ± 5%; p ≤ 0.05). These data support that aging may reduce a1 adrenergic receptor mediated vascular control, altering the vasoconstrictive responsiveness of diaphragm resistance vessels. We are increasing our group sizes to test the robustness of this conclusion. This work was supported by the Sustained Momentum for Investigators with Laboratories Established (SMILE) Grants awarded to T.I.M and D.C.P. by Kansas State University College of Veterinary Medicine and the National Institute on Aging 1R15AG078060 awarded to B.J.B and D.C.P. A.G.H and K.M.S. were financially supported by Ruth L. Kirschstein National Research Service Awards 1F31HL167618-01 and 1F31HL170643-01, respectively. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Understanding How Clinicians Personalize Fluid and Vasopressor Decisions in Early Sepsis Management

Recent sepsis trials suggest that fluid-liberal vs fluid-restrictive resuscitation has similar outcomes. These trials used generalized approaches to resuscitation, and little is known about how clinicians personalize fluid and vasopressor administration in practice. To understand how clinicians personalize decisions about resuscitation in practice. This survey study of US clinicians in the Society of Critical Care Medicine membership roster was conducted from November 2022 to January 2023. Surveys contained 10 vignettes of patients with sepsis where pertinent clinical factors (eg, fluid received and volume status) were randomized. Respondents selected the next steps in management. Data analysis was conducted from February to September 2023. Online Qualtrics clinical vignette survey. Using multivariable logistic regression, the associations of clinical factors with decisions about fluid administration, vasopressor initiation, and vasopressor route were tested. Results are presented as adjusted proportions with 95% CIs. Among 11 203 invited clinicians, 550 (4.9%; 261 men [47.5%] and 192 women [34.9%]; 173 with >15 years of practice [31.5%]) completed at least 1 vignette and were included. A majority were physicians (337 respondents [61.3%]) and critical care trained (369 respondents [67.1%]). Fluid volume already received by a patient was associated with resuscitation decisions. After 1 L of fluid, an adjusted 82.5% (95% CI, 80.2%-84.8%) of respondents prescribed additional fluid and an adjusted 55.0% (95% CI, 51.9%-58.1%) initiated vasopressors. After 5 L of fluid, an adjusted 17.5% (95% CI, 15.1%-19.9%) of respondents prescribed more fluid while an adjusted 92.7% (95% CI, 91.1%-94.3%) initiated vasopressors. More respondents prescribed fluid when the patient examination found dry vs wet (ie, overloaded) volume status (adjusted proportion, 66.9% [95% CI, 62.5%-71.2%] vs adjusted proportion, 26.5% [95% CI, 22.3%-30.6%]). Medical history, respiratory status, lactate trend, and acute kidney injury had small associations with fluid and vasopressor decisions. In 1023 of 1127 vignettes (90.8%) where the patient did not have central access, respondents were willing to start vasopressors through a peripheral intravenous catheter. In cases where patients were already receiving peripheral norepinephrine, respondents were more likely to place a central line at higher norepinephrine doses of 0.5 µg/kg/min (adjusted proportion, 78.0%; 95% CI, 74.7%-81.2%) vs 0.08 µg/kg/min (adjusted proportion, 25.2%; 95% CI, 21.8%-28.5%) and after 24 hours (adjusted proportion, 59.5%; 95% CI, 56.6%-62.5%) vs 8 hours (adjusted proportion, 47.1%; 95% CI, 44.0%-50.1%). These findings suggest that fluid volume received is the predominant factor associated with ongoing fluid and vasopressor decisions, outweighing many other clinical factors. Peripheral vasopressor use is common. Future studies aimed at personalizing resuscitation must account for fluid volumes and should incorporate specific tools to help clinicians personalize resuscitation.

Role of high-volume plasmapheresis in the management of paediatric acute liver failure.

Paediatric acute liver failure (PALF) is a life-threatening disease. Management aims to support hepatic regeneration or to bridge to liver transplantation. High-volume plasmapheresis (HVP) removes protein-bound substances, alleviates inflammation, and improves survival in adult acute liver failure. However, experience with HVP in PALF is limited. Aim of this study is to report on feasibility, safety, efficacy and outcomes of HVP in PALF. Retrospective observational study in children with PALF. HVP was performed upon identification of negative prognostic indicators, in toxic aetiology or multiorgan failure (MOF). Exchanged volume with fresh-frozen plasma corresponded to 1.5-2.0 times the patient's estimated plasma volume. One daily cycle was performed until the patient met criteria for discontinuation, that is, liver regeneration, liver transplantation, or death. Twenty-two children with PALF (body weight 2.5-106 kg) received 1-7 HVP cycles. No bleeding or procedure-related mortality occurred. Alkalosis, hypothermia and reduction in platelets were observed. Haemolysis led to HVP termination in one infant. Seven children (32%) survived with their native livers, 13 patients (59%) underwent liver transplantation. Two infants died due to MOF. Overall survival was 86%. International normalization ratio (INR), alanine aminotransaminases (ALT), bilirubin and inotropic support were reduced significantly (p < 0.05) after the first HVP-cycle (median): INR 2.85 versus 1.5; ALT 1280 versus 434 U/L; bilirubin 12.7 versus 6.7 mg/dL; norepinephrine dosage 0.083 versus 0.009 µg/kg/min. Median soluble-interleukin-2-receptor dropped significantly following HVP (n = 7): 2407 versus 950 U/mL (p < 0.02). HVP in PALF is feasible, safe, improves markers of liver failure and inflammation and is associated with lowering inotropic support. Prospective and controlled studies are required to confirm efficacy of HVP in PALF.

Dose equivalence for metaraminol and noradrenaline - A retrospective analysis.

Noradrenaline and metaraminol are commonly used vasopressors in critically ill patients. However, little is known of their dose equivalence. We conducted a single centre retrospective cohort study of all ICU patients who transitioned from metaraminol to noradrenaline infusions between August 26, 2016 and December 31, 2020. Patients receiving additional vasoactive drug infusion were excluded. Dose equivalence was calculated based on the last hour metaraminol dose (in μg/min) and the first hour noradrenaline dose (in μg/min) with the closest matched mean arterial pressure (MAP). Sensitivity analyses were performed on patients with acute kidney injury (AKI), sepsis and mechanical ventilation. We studied 195 patients. The median conversion ratio of metaraminol to noradrenaline was 12.5:1 (IQR 7.5-20.0) for the overall cohort. However, the coefficient of variation was 77% and standard deviation was 11.8. Conversion ratios were unaffected by sepsis or mechanical ventilation but increased (14:1) with AKI. One in five patients had a MAP decrease of >10mmHg during the transition period from metaraminol to noradrenaline. Post-transition noradrenaline dose (p<0.001) and AKI (p=0.045) were independently associated with metaraminol dose. The proportion of variation in noradrenaline dose predicted from metaraminol dose was low (R2=0.545). The median dose equivalence for metaraminol and noradrenaline in this study was 12.5:1. However, there was significant variance in dose equivalence, only half the proportion of variation in noradrenaline infusion dose was predicted by metaraminol dose, and conversion-associated hypotension was common.

Capillary refill time response to a fluid challenge or a vasopressor test: an observational, proof-of-concept study

BackgroundSeveral studies have validated capillary refill time (CRT) as a marker of tissue hypoperfusion, and recent guidelines recommend CRT monitoring during septic shock resuscitation. Therefore, it is relevant to further explore its kinetics of response to short-term hemodynamic interventions with fluids or vasopressors. A couple of previous studies explored the impact of a fluid bolus on CRT, but little is known about the impact of norepinephrine on CRT when aiming at a higher mean arterial pressure (MAP) target in septic shock. We designed this observational study to further evaluate the effect of a fluid challenge (FC) and a vasopressor test (VPT) on CRT in septic shock patients with abnormal CRT after initial resuscitation. Our purpose was to determine the effects of a FC in fluid-responsive patients, and of a VPT aimed at a higher MAP target in chronically hypertensive fluid-unresponsive patients on the direction and magnitude of CRT response.MethodsThirty-four septic shock patients were included. Fluid responsiveness was assessed at baseline, and a FC (500 ml/30 mins) was administered in 9 fluid-responsive patients. A VPT was performed in 25 patients by increasing norepinephrine dose to reach a MAP to 80–85 mmHg for 30 min. Patients shared a multimodal perfusion and hemodynamic monitoring protocol with assessments at at least two time-points (baseline, and at the end of interventions).ResultsCRT decreased significantly with both tests (from 5 [3.5–7.6] to 4 [2.4–5.1] sec, p = 0.008 after the FC; and from 4.0 [3.3–5.6] to 3 [2.6 -5] sec, p = 0.03 after the VPT. A CRT-response was observed in 7/9 patients after the FC, and in 14/25 pts after the VPT, but CRT deteriorated in 4 patients on this latter group, all of them receiving a concomitant low-dose vasopressin.ConclusionsOur findings support that fluid boluses may improve CRT or produce neutral effects in fluid-responsive septic shock patients with persistent hypoperfusion. Conversely, raising NE doses to target a higher MAP in previously hypertensive patients elicits a more heterogeneous response, improving CRT in the majority, but deteriorating skin perfusion in some patients, a fact that deserves further research.

IMPACT OF NOREPINEPHRINE DOSAGE INCREASE AND VOLUME EXPANSION ON CAPILLARY REFILL TIME IN SEPTIC SHOCK PATIENTS

Background: When evaluating patients with acute circulatory failure, one clinical feature that may be quickly determined at the bedside is the capillary refill time (CRT).Objective: The objective of this observational study was to describe the changes in CRT that occur as a result of volume expansion and increased dosages of norepinephrine, along with related macro-circulatory variables, in patients suffering from septic shock. Study Design: This was an observational study. Setting: The study was conducted at Bahria Town International Hospital Lahore and Services Institute of Medical Sciences. Duration of Study: The study was conducted over six months from January 2, 2023, to July 30, 2023. Methods: We measured mean arterial pressure (MAP), cardiac index (CI), and five consecutive CRT readings in 40 septic shock patients. These measurements were taken before and after a 500 mL saline infusion in 20 patients and before and after an increase in norepinephrine dosage in another 20 patients. Results: The "norepinephrine" group had lower SAPS II and SOFA scores than the "volume expansion" group. When all patients were assessed together, volume expansion significantly lowered heart rate while increasing MAP, diastolic arterial pressure, CI, CVP, and CRT. Fluid-induced increases in CI of ≥ 15% were observed in 11 patients (55%). In fluid responders, fluid infusion significantly raised MAP by 31% (11-49%) and CI by 26% (20-42%). Increased norepinephrine levels may lower CRT in patients with a baseline value of fewer than 3 seconds. Increasing norepinephrine has a low possibility of decreasing CRT in patients with baseline CRT ≥ 3 seconds if the MAP increase is &lt;15%. However, the decrease in CRT is inconsistent in patients with baseline CRT ≥ 3 seconds when norepinephrine increases MAP by ≥ 15%. Univariate regression analysis revealed a correlation between the absolute value of CRT and lactate levels, heart rate, norepinephrine dosage, gender, SAPS II, and ICU mortality. In a multivariate analysis that included all physiological parameters with a p-value &lt;0.1 in univariate linear regression, only lactate upon admission had a significant association with the absolute value of CRT. Conclusion: CRT uncommonly improves with therapy in individuals with septic shock and prolonged CRT when volume expansion raises cardiac output by &lt;15% and increasing the dosage of norepinephrine increases MAP by &lt;15%. CRT's response varies when there are significant effects of fluid infusion on cardiac output and norepinephrine on MAP; in some patients, it decreases while remaining consistent in others. CRT functions as an indicator of microcirculation in this context.