Category Archives: sepsis

Immunotherapies for cancer in the ICU

The first lecture of the day was given by the expert in the area Elie Azoulay.  He talked through immune therapies that are being used in cancer.

Immune therapy “boosts” the immune system and restores its ability to eradicate cancer cells.  There are loads of different types of immune therapy – but Azoulay focussed on the ones that are of relevance to intensivists – Adoptive Cell Transfer, encapsulating “CAR T-cells” and “checkpoint inhibitors”.

Cancer cells normally find ways to act on checkpoints (molecules on T Cells) to avoid being attacked by the immune system.  Checkpoint inhibitors, drugs like pembrolizumab and vivolumab [act on PD-1] or atezolizumab [acts on PD-L1] activate the immune system to get to work on tumours.  BUT the usual safeguards against autoimmunity within the body are also affected.  Other drugs that target CTLA-4 (such as ipilimumab used in melanoma)  act as a type of “off switch” on T Cells.  And they work in solid organ tumours – particularly in combination the oncology trial results are impressive… This paper is an overview of the field from a couple of years ago as quoted below:

There are lots of these drugs – how might you identify if your patient has received one? Well hopefully it will be abundantly clear from their treatment or oncologist – but they are all monclonal antibodies of course so end in -mab.  Heres a list:

The other type of treatment in this category then is Chimeric Antigen Receptor T Cells (CAR-T cells).  These are the patient’s own T Cells, apheresed, stimulated and expanded and then re-infused.

The treatments and trials of note are Tisagenlecuecel in the ELIANA trial for young people with refectory B Cell ALL and JULIET trial for high grade B Cell lymphoma and Axicabtagene cioleucel for relapsed B Cell lymphoma in the ZUMA-I trial.

The reason these second or third line cancer treatment matters for intensive care though is because of the serious adverse event rate.  All this immune system jiggery pokery comes at the cost of upsetting normal function and some 30 to 40% of patients will get some sort of complication:

So what will we need to do on ICU?

The lists of critical care support is quite long as theses patients can get multi organ failure requiring support! They range from ruling out infection (e.g. LP in neurotoxicity – is it CAR-T related or CNS infection/sepsis?) and admiting for close observation/monitoring, good symptom control/IV fluids through to oxygenation and ventilation for acute respiratory failure, vasopressors and shock treatment and even renal and cardiac support and monitoring.  There are specific treatments – steroids are the mainstay but blocking the cytokines responsible for the cytokine storm (for example with IL6 antagonists /  tacilizumab) and other rescue strategies.

Some of the complications are still not fully understood – for example neurotoxicity might be related to the parenchyma effect of CAR-T cells or might be a break down of the blood brain barrier, and earlier onset cytokine storm seems to lead to worse neurotoxicity – prompting some people to think there is a link.  But its still an area of research…

The current reality in many units is that CART therapy is bringing patients to ICU for reversible pathology, and because CAR T therapy is an exciting area, perhaps perhaps it will expand beyond its current remit in cancer to other conditions… So we need to be ready!

My favourite bit of Azoulays talk today was his patient information leaflet – enjoy!

Jamie

ICM Experimental 1: Mechanisms of Multi-organ Failure

How to protect and resuscitate the mitochondrium: Role of Metformin and Cyclosporin

(Jean-Charles Preiser)

3 post-injury phases: Early Phase attempts to protect cellular integrity at the expense of functionality

  • changes in macro / microcirculation
  • decreased oxygen consumption
  • decreased energy expenditure
  • metabolic shutdown

Hyperlactataemia closely related to severity of sepsis; in established sepsis it is defect of oxygen utilisation, rather than impaired oxygen transport

 

Mitochondria in critical illness– more than just a powerhouse – also key roles in cell signalling (ROS), calcium homeostasis, regulation of apoptosis. Stressed mitochondria release DAMPs, further increasing inflammation and systemic toxicity

 

Metformin directly decreases mitochondrial respiration and increases aerobic glycolysis

Several studies have shown improved outcomes associated with metformin use in ITU patients

Cyclosporin A inhibits opening of mitochondrial permeability transition pore (mPTP), thereby preventing cell death

Rabbit model: cardiac arrest –> resuscitation with either 1. Control or 2. Cyclosporin A or 3. Non-immunosuppressive analogue-Inhibitor of mPTP opening –> organs harvested with functional markers recorded

 

Cyclosporin A (and non-immunosuppressive analogue-Inhibitor of mPTP opening) – protective effect on liver, kidney and heart, but not lung

Clinical:

  1. Cyclosporine before PCI for acute MI (800 pts): randomisation to bolus of Cyclosporine or Placebo –> disappointingly same primary outcome (death any cause / cardiac compromise) in both groups   ??dose ??timing-related
  2. Out-of-hospital cardiac arrest (800pts): randomisation to bolus of cyclosporine vs placebo – No difference in SOFA scores 24 hrs post-admission   ??dose ??timing-related ??inclusion criteria

 

Late and Recovery phases post-injury: Long stayers >5 days – decreased mitochondrial biogenesis, dysregulated lipid oxidation –> weakness, muscle inflammation, impaired anabolic recovery

 

Inhibitors of mitochondrial function may prevent later organ failure if given very early post-injury BUT prolonged mitochondrial dysfunction is not desirable

 

Recommended reading: Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence

 

The role of the Glucocorticoid (GC) receptor in circulatory shock

(Sabine Vettorazzi)

 

GC production and function is required for efficient response to inflammation – abnormal GC production associated with higher sepsis mortality in animal models and humans

GC binds to Glucocorticoid receptor (GR) –> translocates to nucleus

  • GR monomer –> Represses inflammation
  • GR dimer –> Induces inflammation

 

GR Dimerisation-deficient mouse model (GRdim) created, to clearly discriminate effects of GR monomers from GR dimers (which are completely absent)

Mice subjected to endotoxin-mediated shock: GRdim mice died faster than wild-type mice

  • more severe lactate acidosis
  • higher inotropic requirement for haemodynamic stability
  • impaired lung compliance
  • increased osteopontin levels (with decreased levels of anti-inflammatory IL-10)

 

GR Dimer is important for survival during LPS induced toxic shock, at least during the first 6 hours of shock in GRdim mice (only observed for 6 hours with intensive care support)

 

Why and how the heart fails

(Alain Rudiger)

 

Four shock states –

  • shock –> cardiac dysfunction, MOF
  • combination of shock states commonly occur

 

Cardiac dysfunction during Inflammatory Shock:

  • Elevated BNP and Troponin
  • Arrhythmia
  • Systolic and diastolic dysfunction

 

Is this myocardial injury the reason for cardiac dysfunction?

Little evidence of myocyte necrosis in pts dying of sepsis + impaired contractility is Reversible = functional impairment rather than structural damage

 

Adaptive myocardial depression when myocardium is at risk

  • reprogramming of genes
  • activation of fetal genes (survival program)
  • decreased energy expenditure to keep cells viable

 

Complex process of gene activation / down regulation in multiple cell-types at different times

 

Rat model 6 hours post-onset of faecal peritonitis:  500+ genes up/down regulated

  • –> downstream: signalling cascades e.g. blunted adrenergic cascade / blunted calcium transport
  • –> further downstream: affects electromechanical coupling and decreases myocardial contractility

 

Close interactions between shock, cardiac dysfunction and MOF

The heart fails as a result of multiple factors:

  • Insufficient preload
  • Excessive RV afterload
  • Arrhythmia, dyssynchrony
  • Diastolic dysfunction and impaired contractility