Benyamen, Julian
(2024)
The potential for repurposing α2-adrenoceptor agonists and noradrenaline uptake1 inhibitors in the management of septic shock.
PhD thesis, University of Nottingham.
Abstract
Background: Septic shock is a life-threatening condition characterised by consistent hypotension caused by vasoplegia, endothelial dysfunction, and abnormal nitric oxide (NO) metabolism, leading to multiple organ failure. It affects more than 48 million people globally each year and is associated with approximately 11 million deaths. The guidelines from the Surviving Sepsis Campaign (SSC) describe early fluid resuscitation and antibiotics as the fundamental treatments of sepsis. However, a large number of patients with sepsis still progress to septic shock with unstable haemodynamic responses, necessitating the use of vasopressors to enhance organ perfusion. Noradrenaline (NA) is the first choice to be used in intensive care units (ICUs), but high doses of NA might lead to adverse cardiac complications such as tachyarrhythmia, peripheral ischaemia, and immunosuppression. A strategy of combining NA with other vasoactive agents has been recently proposed to reduce the required doses or the time spent on NA infusion and to improve the outcomes of sepsis patients in ICU.
Methods: Porcine isolated blood vessels were used in vascular contractility studies of α2-adrenoceptor agonists and NA uptake1 inhibitors, which were dissected and set up in organ baths containing Krebs-Henseleit solution. The effect of dexmedetomidine on endothelial cell permeability was demonstrated using Human Umbilical Vein Endothelial Cells (HUVECs) in tissue culture experiments. In a clinical retrospective cohort study, data from 426 ICU patients at Nottingham University Hospitals (NUHs) were collected to examine the association between clonidine infusion and changes in neutrophils, white blood cells (WBCs), and platelets.
Results: In addition to the central actions of α2-adrenoceptor agonists, they have various peripheral effects including immunosuppressive actions and vasoconstriction. The administration of dexmedetomidine as a sedative agent in ICU patients can potentially improve peripheral vascular resistance and subsequently maintain blood pressure through peripheral vasoconstriction. The present results showed that dexmedetomidine, clonidine, brimonidine, guanfacine, and mivazerol exhibit vasoconstrictive actions in peripheral and central porcine isolated blood vessels. The splenic vein showed higher sensitivity to α2-adrenoceptor agonists compared to the splenic and tail arteries. The combination of NA with dexmedetomidine or guanfacine enhanced NA mediated contractions in porcine splenic arteries. The potency and maximum contraction induced by therapeutic related concentrations of NA (1 nM - 200 nM) were enhanced in the presence of 10 nM dexmedetomidine or 100 nM guanfacine. The -Log EC30 KCl of NA increased from 7.06 ± 0.07 to 7.40 ± 0.09 (p-value < 0.0001), and from 6.92 ± 0.06 to 7.63 ± 0.10 (p-value < 0.001) in the presence of dexmedetomidine and guanfacine, respectively. Dexmedetomidine (50 µM) showed protective action on LPS induced endothelial cell hyperpermeability in HUVECs. Therapeutically relevant concentrations of NA uptake1 inhibitors such as atomoxetine, reboxetine, and desipramine enhanced the EFS induced contraction by increasing the time duration to 50% relaxation in porcine splenic and renal arteries. The combination of NA with atomoxetine 100 nM enhanced NA mediated contractions, where the Log EC30 KCl of NA increased from 7.06 ± 0.06 to 7.43 ± 0.07 (p-value < 0.01). The retrospective cohort study demonstrated that there was no significant difference in the levels of neutrophils, WBCs, and platelets between the clonidine and control groups. The hospital survival rate was significantly higher in the clonidine group compared to the control group (p-value < 0.05).
Conclusion: The vasoconstrictive effects of α2-adrenoceptor agonists suggest that using dexmedetomidine and clonidine as sedatives in ICU might have additional non-sedative actions involving the immune system and cardiovascular system, potentially benefiting the management of sepsis.
Dexmedetomidine and guanfacine demonstrated NA-sparing effects by reducing the required NA dosage by 50%. NA uptake1 inhibitors enhanced the duration of vasoconstriction induced by endogenous NA, and coadministration of atomoxetine with exogenous NA produced NA-sparing effects. In ICU patients, clonidine infusion was associated with increased hospital survival despite no changes in the levels of neutrophils, platelets, and WBCs.
| Item Type: |
Thesis (University of Nottingham only)
(PhD)
|
| Supervisors: |
Wilson, Vincent
Smith, Paul
Beed, Martin |
| Keywords: |
Septic shock; α2-adrenoceptor agonists; Vasoactive agents; Vasoconstriction |
| Subjects: |
Q Science > QP Physiology |
| Faculties/Schools: |
UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences |
| Item ID: |
79972 |
| Depositing User: |
Benyamen, Julian
|
| Date Deposited: |
11 Dec 2024 04:40 |
| Last Modified: |
11 Dec 2024 04:40 |
| URI: |
https://eprints.nottingham.ac.uk/id/eprint/79972 |
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