Different Doses Of Norepinephrine Research Articles

Dose-related effects of norepinephrine on early-stage endotoxemic shock in a swine model

BackgroundThe benefits of early use of norepinephrine in endotoxemic shock remain unknown. We aimed to elucidate the effects of different doses of norepinephrine in early-stage endotoxemic shock using a clinically relevant large animal model. MethodsVasodilatory shock was induced by endotoxin bolus in 30 Bama suckling pigs. Treatment included fluid resuscitation and administration of different doses of norepinephrine, to induce return to baseline mean arterial pressure (MAP). Fluid management, hemodynamic, microcirculation, inflammation, and organ function variables were monitored. All animals were supported for 6 h after endotoxemic shock. ResultsInfused fluid volume decreased with increasing norepinephrine dose. Return to baseline MAP was achieved more frequently with doses of 0.8 µg/kg/min and 1.6 µg/kg/min (P <0.01). At the end of the shock resuscitation period, cardiac index was higher in pigs treated with 0.8 µg/kg/min norepinephrine (P <0.01), while systemic vascular resistance was higher in those receiving 0.4 µg/kg/min (P <0.01). Extravascular lung water level and degree of organ edema were higher in animals administered no or 0.2 µg/kg/min norepinephrine (P <0.01), while the percentage of perfused small vessel density (PSVD) was higher in those receiving 0.8 µg/kg/min (P <0.05) and serum lactate was higher in the groups administered no and 1.6 µg/kg/min norepinephrine (P <0.01). ConclusionsThe impact of norepinephrine on the macro- and micro-circulation in early-stage endotoxemic shock is dose-dependent, with very low and very high doses resulting in detrimental effects. Only an appropriate norepinephrine dose was associated with improved tissue perfusion and organ function.

Hemodynamic evaluation by serial right heart catheterizations after cardiac arrest; protocol of a sub-study from the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX)

BackgroundNeurological injury and mortality remain high in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). Hypotension and hypoxia during post-resuscitation care have been associated with poor outcome, but the optimal oxygenation- and blood pressure-targets are unknown. The impact of different doses of norepinephrine on advanced hemodynamic after OHCA and the impact of different oxygenation-targets on pulmonary circulation and resistance (PVR), are unknown. The aims of this substudy of the “Blood pressure and oxygenations targets after out-of-hospital cardiac arrest (BOX)”-trial are to investigate the effect of two different MAP- and oxygenation-targets on advanced systemic and pulmonary hemodynamics measured by pulmonary artery catheters (PAC). MethodsThe BOX-trial is an investigator-initiated, randomized, controlled study comparing targeted MAP of 63 mmHg vs 77 mmHg (double-blinded intervention) and 9–10 kPa versus PaO2 of 13–14 kPa oxygenation-targets (open-label). Per protocol, all patients will be monitored systematically with PACs. The primary endpoint of the hemodynamic-substudy is cardiac output for the MAP-intervention, and PVR for the oxygenation-intervention. For both endpoints, the difference within 48 h between groups are assessed. Secondary endpoints are pulmonary capillary wedge pressure and pulmonary arterial pressure and association between advanced hemodynamic variables and mortality and biomarkers of inflammation and brain injury. DiscussionIn the BOX-trial, patients will be randomly allocated to two levels of MAP and oxygenation, which are central parts of post-resuscitation care and where evidence is sparse. The advanced-hemodynamic substudy will give valuable knowledge of the hemodynamic consequences of changing blood pressure and oxygen-levels of the critical cardiac patient. It will be one of the largest clinical, prospective trials of advanced hemodynamics measured by serial PACs in consecutive comatose patients, resuscitated after OHCA. The randomized and placebo-controlled trialdesign of the MAP-intervention minimizes risk of selection bias and confounders. Furthermore, hemodynamic characteristics and associations with outcome will be investigated. Trial registrationClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT03141099). Registered March 30, 2017.

Prophylactic co-administration of two different bolus doses of norepinephrine in spinal-induced hypotension during caesarean section: A prospective randomized double-blinded study

Background: Vasopressors for prophylaxis and treatment of spinal hypotension have grown in popularity in recent years. Norepinephrine is now emerging as one of the feasible options for prevention as well as management of spinal-induced hypotension in caesarean section (CS). The aim of our study was to compare the efficacy of two different doses of norepinephrine as prophylaxis for spinal-induced hypotension during CS. Material and Methods: Total 110 patients were recruited in this prospective randomized double-blind study from December 2017 to June 2019. After fulfilling the inclusion and exclusion criteria, this study was conducted on 90 patients undergoing elective CS under spinal anesthesia, who were assigned into three groups of 30 patients each. Group N6received norepinephrine 6 μg as an intravenous bolus, group N4received norepinephrine 4 μg, and group C received normal saline simultaneously with subarachnoid block. Incidence of hypotension, requirement of rescue doses of norepinephrine, time of first rescue dose, hemodynamic parameters, adverse effects, and neonatal complications were assessed, compared and analyzed. Results: The incidence of post spinal hypotension was 63.33% in group N6, 80% in group N4, and 83.33% in group C (p = 0.155). Total rescue dose requirement of norepinephrine was significantly less in group N6(8.21 ± 2.97 μg) as compared to N4(9.00 ± 3.06 μg) and control group (11.00 ± 4.57 μg).(p = 0.011). The median time to first rescue dose requirement of norepinephrine was significantly delayed in group N6(6[8–4.5] min) and group N4(4[9–2.5] min) as compared to control group (4[5–2] min) (p = 0.004). Conclusion: Prophylactic intravenous bolus dose of 6 μg norepinephrine when co-administered with spinal anesthesia was found to be more effective than 4 μg norepinephrine in terms of decreasing total rescue dose requirement of vasopressor and delaying the time to first rescue dose, without significant change in the incidence of hypotension.

Noradrenergic mechanism involved in the nociceptive modulation of nociceptive-related neurons in the caudate putamen

Norepinephrine (NE) participates in pain modulation of the central nervous system. The caudate putamen (CPu) is one region of the basal ganglia that has been demonstrated to be involved in nociceptive perception. Our previous work has shown that microinjection of different doses of norepinephrine into the CPu produces opposing effects in the tail-flick latency (TFL) of rats. However, the mechanism of action of NE on the pain-related neurons in the CPu remains unclear. The present study examined the effects of NE and the alpha-adrenoceptor antagonist phentolamine on the pain-evoked response of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the CPu of rats. Trains of electric impulses were used for noxious stimulation, and were applied to the sciatic nerve. The electrical activities of pain-related neurons in the CPu were recorded by a glass microelectrode. The results revealed that intra-CPu microinjection of NE (8 μg/2 μl) increased evoked firing frequency of PEN and shortened the firing latency, but decreased the evoked firing frequency of PIN and prolonged the inhibitory duration (ID). Intra-CPu administration of phentolamine (4 μg/2 μl) showed the opposite effects. The above results suggest that NE in the CPu modulates nociception by affecting the baseline firing rates of PENs and PINs.

Microinjection of different doses of norepinephrine into the caudate putamen produces opposing effects in rats

It has been proven that norepinephrine (NE) regulates antinociception through its action on alpha-adrenoceptors located in brain nuclei, spinal cord, and peripheral organs. However, the supraspinal mechanism of noradrenergic pain modulation is controversial. The present study was aimed at investigating the nociceptive effects induced by injecting different doses of NE and phentolamine into the caudate putamen (CPU) of rats. The thermal pain threshold of the rats was measured by performing a tail-flick test. The tail-flick latency (TFL) was measured at 2-60 min after microinjection of the drugs. Our results revealed that the thermal pain threshold increased (long TFL) after the administration of a low dose of NE (2 microg/2 microl) and decreased (short TFL) after injection of a high dose of NE (8 microg/2 microl). In contrast, the pain threshold decreased after the administration of a low dose of phentolamine (1 microg/2 microl), while it increased after injection of a high dose of phentolamine (4 microg/2 microl). These results indicated that the injection of different doses of NE in the CPU of the rats produced opposite effects on the pain threshold, as determined by the tail-flick tests.

Improved Survival after Resuscitation with Norepinephrine in a Murine Model of Uncontrolled Hemorrhagic Shock

Recent studies have challenged current guidelines on fluid resuscitation. However, studies on resuscitation using norepinephrine in uncontrolled hemorrhagic shock are lacking. The authors examined the effects of norepinephrine in combination with saline infusion in uncontrolled hemorrhage in rats. Rats subjected to a 15-min controlled hemorrhage (withdrawal of 3 ml blood/100 g body mass) followed by a 60-min uncontrolled hemorrhage (75% tail amputation) were randomly assigned to one of several treatment groups (10 rats/group) receiving different doses of norepinephrine (0 [NE0], 5 [NE5], 50 [NE50], or 500 [NE500] microg.100 g(-1).h(-1)). In the four hypotensive resuscitation groups (n = 40), mean arterial pressure was not allowed to fall below 40 mmHg by titrated infusion of normal saline. In the four normotensive resuscitation groups (n = 40), it was not allowed to fall below 80 mmHg. The endpoint was survival at 210 min. There was a significant difference (P < 0.05) in survival rate among groups. Among the hypotensive rats, 6 (60%) survived in the NE0 and NE5 dose groups, 9 (90%) survived in the NE50 dose group, and none survived in the NE500 dose group. Among the normotensive rats, none survived in the NE0 group, 4 (40%) survived in the NE5 dose group, all 10 (100%) survived in the NE50 group, and none survived in the NE500 group. The early use of norepinephrine in uncontrolled hemorrhagic shock in rats significantly improved survival when infused at a rate of 50 microg.100 g(-1).h(-1) in normotensive and hypotensive resuscitation strategies.

This Month in Anesthesiology

In awake patients undergoing carotid endarterectomy, stump pressure monitoring, near-infrared spectroscopy, and transcranial Doppler sonography provide similar accuracy for the detection of cerebral ischemia.Vocal cord sequelae after fiberoptic intubation with a flexible silicon tube were similar to conventional tracheal intubation.Poor agreement between American College of Cardiology/American Heart Association guideline recommendations for perioperative care and daily clinical practice.See the accompanying Editorial View on page 526 The December 2001 Food and Drug Administration (FDA) black box warning about droperidol, commonly used as premedication for postoperative nausea and vomiting, was based on 10 case reports. To determine the true incidence of QTc prolongation and/or drug-induced torsade de pointes (TdP) associated with droperidol use, Nuttall et al. conducted a retrospective study using the electronic Anesthesia Quality Assurance database at their institution. They reviewed charts of surgical patients from three years prior to December 2001 and from three years after the FDA warning. Prior to the black box warning, 12% of patients received droperidol for antiemesis; none were administered droperidol after the warning. Of an estimated 16,791 patients exposed to droperidol, none experienced documented torsade de pointes. In light of these findings, the FDA warning may be excessive and unnecessary for low-dose droperidol therapy. See the accompanying Editorial View on page 524 Poloujadoff et al. subjected rats to uncontrolled hemorrhagic shock to test the efficacy of norepinephrine for resuscitation. Different doses of norepinephrine (from 0 to 500 μg · 100 g−1· h−1) were given in four hypotensive and four normotensive resuscitation groups, and animals were observed for 210 min posthemorrhage. Rats treated with high doses of norepinephrine died early. Survival significantly improved when norepinephrine was infused early at a rate of 50 μg · 100 g−1· h−1in both the normotensive and hypotensive resuscitation groups. More widely available than vasopressin, norepinephrine might be a useful strategy in resuscitation after hemorrhagic shock. See the accompanying Editorial View on page 529 In some children, midazolam does not relieve presurgery anxiety. Kain et al. administered a series of behavioral tests, including the modified Yale Preoperative Anxiety Scale (mYPAS), to children scheduled for surgery and their parents. Based on the mYPAS and other scores, 14.1% of the children were nonresponders to midazolam. Correlation analysis revealed that these children tended to be younger, more emotional, and more anxious at baseline. Alternative anxiety-reducing strategies, including behavioral techniques, may be in order for this subgroup of children before surgery.Patients over the age of 65 scheduled for coronary artery bypass surgery were randomized to receive moderate (hematocrit ≥ 27%) or profound (hematocrit 15–18%) hemodilution during cardiopulmonary bypass. Authors Mathew et al. measured the patients' cognitive function preoperatively and 6 weeks postoperatively, to determine the effects of hemodilution on cognition. The trial was terminated after randomization of only 108 patients due to significant pulmonary complications evidenced in the moderate hemodilution group. In the patients who did complete the study, greater neurocognitive impairment was observed in those older patients receiving extreme hemodilution.This article has been selected for the Anesthesiology CME Program.

Norepinephrine in low to moderate doses may not increase luminal concentrations of l‐lactate in the gut in patients with septic shock*

To investigate the effect of different doses of norepinephrine (noradrenaline) on luminal concentrations of L-lactate in the rectum and stomach in patients with fluid-resuscitated septic shock. This was a paired cross-over study in which the dose of norepinephrine was titrated to mean arterial blood pressures (MAPs) of 65 and 85 mmHg in random sequence. It was performed in a mixed intensive care unit at a university hospital. Eight patients with fluid-resuscitated septic shock requiring norepinephrine (>0.1 microg/kg/min) were included. Patients were treated with norepinephrine to a MAP of either 65 or 85 mmHg for 2 h. After a 'washout' period of 2 h, the dose of norepinephrine was titrated to the other endpoint of MAP for another 2 h. The concentrations of L-lactate in the rectal and gastric lumen were estimated by 1-h equilibrium dialysis during the second hour of the treatment periods. MAP and central venous oxygen saturation were increased by increasing the dose of norepinephrine [median (range) (microg/kg/min): 0.07 (0.00-0.60) and 0.18 (0.11-1.00) at MAPs of 65 and 85 mmHg, respectively], whereas the metabolic markers were unaffected [luminal concentrations (mmol/l) of L-lactate in the rectum of 1.9 (0.8-6.4) and 1.8 (0.9-5.7) (P =0.94) and in the stomach of 1.1 (0.1-10.0) and 1.3 (0.3-9.7) (P =0.88) at MAPs of 65 and 85 mmHg, respectively]. In this small study, luminal concentrations of L-lactate in the rectum and stomach were unaffected by norepinephrine at low to moderate doses. These data suggest that norepinephrine may not increase luminal concentrations of l-lactate in the gut in patients with fluid-resuscitated septic shock.

Arginine Vasopressin in Vasodilatory Shock

To the Editor: Dunser et al1 concluded that the combined infusion of vasopressin and norepinephrine is superior to infusion of norepinephrine alone in the treatment of shock resistant to catecholamine. We believe that this study is flawed and do not support such a conclusion. First of all, the design included two interventions in parallel, one of arginine vasopressin (and its control group in the other arm, without such treatment) and the other with two different doses of norepinephrine. They concluded that the combination group required a lower dose of norepinephrine, which was a consequence of the experimental protocol. The major shortcoming of this study, however, is an evident mistake in the statistical interpretation of their main results. The authors concluded that patients treated with the combination had improved cardiac performance, an effect that did not occur at all. Table 2 of …

Heart rate dynamics during accentuated sympathovagal interaction.

Concomitant sympathetic and vagal activation can occur in various physiological conditions, but there is limited information on heart rate (HR) behavior during the accentuated sympathovagal antagonism. Beat-to-beat HR and blood pressure were recorded during intravenous infusion of incremental doses of norepinephrine in 18 healthy male volunteers (mean age 23 +/- 5 yr). HR and blood pressure spectra and two-dimensional Poincaré plots were generated from the baseline recordings and from the recordings at different doses of norepinephrine. The mean blood pressure increased (from 90 +/- 7 to 120 +/- 9 mmHg, P < 0.001), HR decreased (from 60 +/- 9 to 48 +/- 7 beats/min, P < 0.001), and the high-frequency spectral component of HR variability increased (P < 0.001) during the norepinephrine infusion as evidence of accentuated sympathovagal interaction. Abrupt aperiodic changes in sinus intervals that were not related to respiratory cycles or changes in blood pressure occurred in 14 of 18 subjects during the norepinephrine infusions. These fluctuations in sinus intervals resulted in a complex or parabola-shaped structure of the Poincaré plots of successive R-R intervals and a widening of the high-frequency spectral peak. In four subjects, the abrupt fluctuations in sinus intervals were followed by a sudden onset of fixed R-R interval dynamics with a loss of respiratory modulation of HR, resulting in a torpedo-shaped structure of the Poincaré plots. These data show that HR behavior becomes remarkably unstable during accentuated sympathovagal interaction, resembling stochastic dynamics or deterministic chaotic behavior. These features of HR dynamics can be better identified by dynamic analysis of beat-to-beat behavior of R-R intervals than by traditional analysis techniques of HR variability.

An in vitro study of ectopic discharge generation and adrenergic sensitivity in the intact, nerve-injured rat dorsal root ganglion

A chronic, loose constriction of the sciatic nerve in rat produces behavioral signs of spontaneous pain and cutaneous hyperalgesia (Bennett and Xie, Pain, 33 (1988) 87–107) as well as an abnormal spontaneous activity and adrenergic sensitivity of certain dorsal root ganglion (DRG) cells with axons in the injured nerve (Kajander et al., Neurosci. Lett., 138 (1992) 225–228; Xie et al., J. Neurophysiol., 73 (1995)1811–1820) The present study investigated whether the spontaneous activity and adrenergic sensitivity were intrinsic properties of injured DRG cells and manifested in vitro, i.e., not dependent on intact blood circulation and an intact, functioning sympathetic nervous system. Two weeks after a loose constriction of the sciatic nerve, the L4 or L5 DRG with its ligated nerve and dorsal root attached was removed from the rat and placed in a chamber. Extracellular recordings were made from teased dorsal root fibers. Spontaneous activity (>0.05 imp/s in 3 min) originating within or close to the DRG was often found in C-, A δ- and A β-fibers from nerve-injured rats, but was rare in fibers with peripheral axons from uninjured nerve. The incidence of various patterns of spontaneous discharge was similar to that previously recorded in vivo. Nineteen of 30 C-fibers, four of five A δ- and three of seven A β-fibers from injured nerve responded to different doses of norepinephrine (NE) applied topically to the DRG. Five of seven C- and one of two A β-fibers from injured nerve responded to clonidine, a more selective α 2 adrenergic agonist. The thresholds ranged from 500 to 10 μM, the lowest dose delivered. None of the fibers from uninjured nerve responded to NE or clonidine (500 μM). Since the experiments were carried out in vitro in the intact DRG, the existence of spontaneous activity in DRG cells in nerve-injured rats was independent of any blood borne chemicals, such as norepinephrine. We hypothesize that abnormal activity and adrenergic sensitivity in injured DRG neurons are due to an intrinsic alteration of the cell body membrane.