Assessment 1: The Journal of Biological Chemistry

Guide abstract

All cells within the body are bathed in a fluid. The composition of this fluid is tightly regulated to contain specific levels of various ions. Disruption in the balance of these ions can lead to cell death and damaging inflammation. However, standard surgical practice fails to consider these ionic imbalances. Current practice is to regularly irrigate the surgical site with saline – 0.9% NaCl (table salt) solution. This is to minimize dehydration of the tissue and improve visibility, however, saline is a very poor approximation of the extra-cellular fluid. Our preliminary data show that the use of saline is likely exacerbating tissue damage, causing inflammation, and may be directly toxic. Changes to the irrigation fluid may result in substantial improvement in patient outcomes following surgery. Therefore, this research project will develop a better irrigation fluid through the following aims.

Aim 1: Establish the damaging and inflammatory nature of saline using cell culture, living brain slices and animal models.

Aim 2: Develop an optimal irrigation fluid through iterative alterations to its composition and evaluating improvement through preclinical models.

Aim 3: Determine an optimal biomarker of saline induce tissue damage and inflammation through the analysis of irrigation fluid collected during clinical neurosurgery.

Guide Introduction

In 1885, Dr. Sydney Ringer sought to understand the ionic composition of the extracellular fluid. Using ex vivo beating frog hearts, he established the concentrations of calcium, potassium, sodium and chloride ions needed to maintain normal tissue function. Dr. Ringer developed an artificial analogue of this fluid, now referred to as Ringer’s solution. In 1896, Dr Hartog Hamburger sought to quantify what concentration of NaCl dissolved in water prevented the lysis of red blood cells. From this, the composition of saline was established- 0.9%NaCl in water. For unknown reasons, saline became the clinical standard of fluid replacement and tissue irrigation over the more physiologically accurate Ringer’s solution. However, this decision may have been a deadly one. For example, a 2018 study of over 15,000 intensive care patients found that using Ringer’s solution as an intravenous fluid replacement instead of saline lowered patient mortality from 11.1% to 10.3%. There are a range of potential mechanisms that explain saline’s potential toxicity including the induction of damaging inflammation.

Inflammation is a normally beneficial response by the body to tissue damage or infection. However, when inflammation is excessive it can exacerbate tissue damage, therefore, its mitigation is critical during medical procedures, particularly neurosurgery due to the sensitive nature of the brain.

We have found that saline induces rapid cell death and inflammation which was completely prevented through the addition of potassium to the fluid (fig.1).  This form of inflammation has been clinically associated with vascular pathology and febrile seizures, and preclinically associated with worse stroke and traumatic brain injury outcomes5, 6. Therefore, we hypothesise that the use of saline exacerbates neuroinflammation and this results in worse patient outcomes. However, the exact physiological effects of saline have not been thoroughly investigated. Therefore, to fully understand the negative effects of saline and develop an improved irrigation fluid in the context of neurosurgery we will address the following aims.

Aim 1: Establish the damaging and inflammatory nature of saline using cell culture, living brain slices and animal models.

To gain a deep understanding of the pathophysiological processes occurring during saline exposure we will utilize primary neuronal and microglia cell cultures to investigate the cell death and inflammatory pathways involved using molecular and pharmacological methods established in our laboratories. We will then establish the time course of dysfunction and death of neurons by taking direct neuronal activity recordings in ex vivo living rodent brain slices, tracking dysfunction and death as the irrigation fluid is changed from artificial cerebral spinal fluid (aCSF, a modified Ringer’s solution) to saline. Finally, we will translate this research to an accurate rodent model of surgical tissue damage. During neurosurgical procedures bleeding is minimized through the cauterisation of surface blood vessels. To model this, we will cauterise the distal middle cerebral artery, and irrigate the surrounding area with either saline or aCSF. Following recovery, tissue damage, behavioural changes and inflammation will be measured using established methods in our laboratories.  

Aim 2: Develop an optimal irrigation fluid through iterative alterations to its composition and evaluating improvement through preclinical models.

Figure 2: Calcium increases inflammatory signalling through IL-1α. Microglia incubated with the damage associated molecular pattern (DAMP) -ATP with and without calcium (Ca2+).

While aCSF is an obvious choice for an improved irrigation fluid for neurosurgeries, it is likely that it is not the optimal composition. aCSF contains calcium which is essential for the release of the potent inflammatory cytokine IL-1α (fig.2) and for neuronal excitation, both of which may be detrimental under neurosurgical conditions. Additionally, aCSF contains glucose, and glucose levels have been correlated with worse outcomes following brain tissue damage due to exacerbating inflammatory responses and the production of reactive oxygen species. Therefore, we will develop irrigation fluids that are modified to minimise potentially harmful processes which are dependent on components of extracellular fluid. For this we will initially screen concentration gradients of potential components using high through-put cell models (neuronal, astrocyte and microglial), establishing optimal concentrations of each irrigation fluid component based on minimising inflammation and cell death. From this, we will generate several new putative irrigation fluids. We will then further screen the top irrigation fluid candidates in ex vivo brains slices to select the single best novel irrigation fluid. We will then compare the novel irrigation fluid with saline and aCSF in the rodent model of neurosurgery described in aim-1, with tissue damage, behavioural changes and inflammation has our end-point measures.

Aim 3: Determine an optimal biomarker of saline induce tissue damage and inflammation through the analysis of irrigation fluid collected during clinical neurosurgery.

Before we can propose changing clinical practice, we must first establish that saline irrigation in surgery leads to inflammation and neuronal death. Furthermore, for this work to be translated to a clinical trial, we must refine methods of analysing clinical samples for markers of saline induced inflammation and cell death.

Dr. Dubey and the neurosurgical team perform aneurysm clipping surgeries weekly. During this procedure, they use saline as an irrigation fluid and collect this saline through a surgical suction apparatus. We have established that inflammation and cell death begin immediately after saline exposure (fig.1). Therefore, this fluid, which is applied intermittently, will contain proteins associated with cell death and inflammation. In collaboration with Dr. Richard Wilson, we will perform proteomic mass spectroscopy. Through this we will be able to establish what proteins are most abundant in the fluid and what biological pathways are being induced by the saline. Additionally, in collaboration with Professor Anna King and Dr. Jessica Collins, we will use Single Molecule Array (SIMOA) technology to probe the irrigation fluid for established and novel markers of neuronal and astrocyte death, and inflammation. SIMOA will allow the detection of a few selected proteins at concentrations several orders of magnitude lower than the proteomic methods.

Collectively this aim will establish a clinical measure of tissue damage from the irrigation fluid which can be used in a future clinical trial to evaluate the efficacy of the novel irrigation fluid developed in aim-2.

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