Fields: 

  • Anaesthesiology
  • Surgery and subspecialties
  • Trauma and critical care

 

Location:

St Lucia campus 

Type of student: 

PhD or MPhil only (includes intercalated PhD & MPhil and Concurrent MPhil) 

Type of work:

Clinical work 
Literature review 
Statistical analysis 
Wet lab work 

Brief synopsis:

Studies of Changes in Microcirculation in Haemorrhage and Resuscitation

PhD Proposal outline

Introduction

Haemorrhage is the leading cause of preventable death after traumatic injury. Most of these deaths are due to uncontrollable haemorrhage and exsanguination but others occur later and on background of multiorgan dysfunction syndrome (MODS). MODS has been shown in clinical studies to be associated with microcirculatory hypoperfusion in the later stages of treatment in the intensive care unit. The microcirculation consists of vessels with an approximate diameter of 5-10 μm and is that part of the circulations where metabolic exchange  with the tissues occurs.

There is evidence that microcirculatory flow does not necessarily always follow macrocirculatory haemodynamics, and attention directed specifically towards the microcirculation may be warranted when treating patients with shock and critical illness. Both flow reduction and heterogeneity of flow between regions are likely to be of clinical significance during shock.

Poor microcirculatory flow indices are also associated with endothelial cell damage and glycocalyceal shedding. How the early stages of shock and resuscitation influence both the microcirculation, the endothelium and glycocalyx are poorly understood.

Since perfusion in the microcirculation is a product of the characteristics of the vessels (tone, patency) and the  intraluminal contents (pressure and rheology), it is likely that microcirculatory flow is related to the behaviour and state of the endothelial lining. 

Understanding the functional anatomy of the endothelial layer within the microcirculation is necessary for a fuller understanding of the mechanisms and behaviour during both the healthy and shocked states and response to resuscitation strategies.

This has important clinical implications in the assessment, monitoring and resuscitation of patients after haemorrhage. Human clinical studies have performed mainly assessing the sublingual microcirculation with videomicroscopy. How this reflects the microcirculation in other vascular bed and the time course to changes and response to resuscitative manoeuvres is unclear. In human trauma the resuscitation strategies adopted, especially with respect to the type of fluid and the adoption of permissive hypotension and their impact on the microcirculation has not been well defined.

 

Aim

The aim of this proposal is to characterise an animal microcirculatory model against human microcirculation. This model will then be used to investigate the responses of different vascular microcirculatory beds to haemorrhage and resuscitation.

 

Objectives

1.     To assess normal human sublingual microcirculation variation in time, age, height, weight and gender.

2.     To compare human sublingual microcirculation with anaesthetised pig and establish model for microcirculatory changes in haemorrhagic shock.

3.     Examine the time course of microcirculatory changes in the sublingual and gastrointestinal vascular beds in anaesthetised pig undergoing controlled haemorrhage and restoration of the circulation with autologous whole blood.

4.     Compare this time course with other resuscitation fluid strategies including crystalloid, plasma, 1:1 packed red cells to plasma, 1:2 packed red cells to plasma.

5.     To measure the circulating syndecan-1 and thrombomodulin as markers of endothelial activation within the systemic and portal circulation and lactate as global measure of hypoperfusion.

 

Methods

1.     Normal human studies will be performed after ethical approvals, on consented volunteers and measurements taken in the Applied Clinical Anatomy Laboratory, UQ School of Biomedical Sciences, St Lucia. This work is to compare baseline sublingual microcirculation in human and pig model.

2.     Animal experiments will conducted at the UQ School of Veterinary Sciences, Gatton after ethical approval.

a.     Animals randomised to experimental group in a 32 factorial design (shock and resuscitation). Analysis with ANOVA.

b.     Animals anaesthetised, monitoring established with pulse, invasive BP, cardiac output. Surgical preparation: splenectomised (to prevent autotransfusion), systemic and portal venous cannulation, small area of colon exteriorised as a stoma).

c.     Controlled haemorrhage to target systolic BP (80mmHg?) in non-sham groups.

d.     Resuscitation strategy implemented after time of shock dependent on group. Resuscitation to 90% pre-haemorrhage systolic BP.

e.     The videomicroscopy system will be a cytocam. Macrocirculatory measures and sublingual and colonic mucosal microcirculation examined every 30 minutes.

f.      Systemic and portal circulation sampled every 30 minutes, blood spun and plasma stored at -80°C.

 

 

Experimental Groups

 

 

 

Sham = no haemorrhage or shock) n=6

 

 

 

 

Resuscitation

Exp 1 = 1 hour shock

Whole blood (n=6)

Plasma (n=6)

Crystalloid (n=6)

Exp 2 = 2 hour shock

Whole blood (n=6)

Plasma (n=6)

Crystalloid (n=6)

Exp 3 = 4 hour shock

 

Whole blood

(n=6)

Plasma (n=6)

Crystalloid (n=6)

 

Circulatory and plasma measurement intervals:

 

T0 = pre-surgical preparation (no colonic microcirculation or portal plasma sampling)

T30 = post-surgical preparation

T60 = post-surgical preparation

Shock Phase

Shock 30, 60, 120 (Exp 2 & 3), 240 (Exp3)

Resus 30, 60, 90, 120

 

Prerequisite skills: None

Time frame: N/A

Website: N/A

Supervisor

Professor Mark Midwinter

Professor in Clinical Anatomy
School of Biomedical Sciences