UK donation and transplantation, 2012

UK donation and transplantation, 2012
Organ Retrieval Workshop, Oxford, November 2012

Narrowing the gap Increase deceased donor numbers
Reduce end stage organ failure Promote alternative sources / solutions Increase organs utilised per donor Donor optimisation Graft re-conditioning Improve graft longevity Failure to maximise the gift of donation dishonours both donors and their families Organ Retrieval Workshop, Oxford, November 2012

Heart transplant rates, 2010
If the vision is ‘every organ, every time’, the reality is that ‘we lose more than we use’ Brain – death – 30 years of general medical and legal acceptance of the diagnosis despite ongoing controversies Cardiac criteria – longstanding acceptance and well understood by the public And the orthopaedic criteria – the most final Worth noting that the definition is brain based and the other 2 criteria are used as surrogates for determining that irreversible loss of brain stem function has or will occur Here is almost reflex checks done – a corpse with rigor is still checked for a pulse and absent respiration by the houseman confirming death; in cardiorespiratory arrest we still look at the pupils Organ Retrieval Workshop, Oxford, November 2012 3

Phases of graft injury Organ Retrieval Workshop, Oxford, November 2012
We are all aware that organs may deteriorate after transplantation, and that so-called marginal grafts are more at risk than ideal ones. We also know that organs may deteriorate whilst on ice We are perhaps less well aware that organs may deteriorate even before retrieval, and for a variety of reasons Organ Retrieval Workshop, Oxford, November 2012

Pre-retrieval graft injury

Organ damage in the DBD donor
Causes of organ impairment The brain dead organ donor has a distinct collection of acute physiological disturbances that are almost always correctable Primary pathology Chronic co-morbidities Brain resuscitation therapies Pathophysiology of brain death Fluid and electrolyte disturbance Haemodynamic instability Neurogenic pulmonary oedema Endocrine dysfunction Systemic inflammation So why do only a minority of offered donor organs ever get used. It may be because of they have been injured as part of the primary injury that has resulted in the donors death It may be because of complicating medical co-morbidities It may ne the damage that the organs have suffered as part of the critical care treatments of the patient’s final illness Or it may be a consequence of the various physiological consequences of brainstem ischaemia: and it is the haemodynamic instability, and how best to manage it, that is the focus of our attention now Fatty kidney from an obese hypertensive donor Organ Retrieval Workshop, Oxford, November 2012

Cause of death in UK DBD donors
% Donor cause of death Organ Retrieval Workshop, Oxford, November 2012

Ages of deceased donors in the UK, 2001-11
Our potential donors are getting older and they will come with more co-morbidity Organ Retrieval Workshop, Oxford, November 2012

BMI of deceased donors in UK, 2001-11

Effect of donor age on organ retrieval in UK
And as our donors age, their apparent donation – transplant – potential falls off Organ Retrieval Workshop, Oxford, November 2012

Principles of brain resuscitation
Therapies for the acutely injured brain deep sedation Intubation and controlled ventilation maintenance of brain perfusion pressure Osmotherapy (ICP) Vasoconstrictors (MAP) Its for others to decide whether anything can be done about this – I want to talk to you about other, more immediate influences, starting with the potential harm that brain resuscitation therapies might represent. The principles of these treatments are straightforward Deep sedation Controlled ventilation Maintenance of brain perfusion pressure through a combination of osmotherapy to reduce the ICP and vasoconstrictors to maintain the MAP Brain-directed therapies take precedence over systemic support Organ Retrieval Workshop, Oxford, November 2012

Principles of brain resuscitation ICP monitoring
The real complications of ICP monitoring cardiovascular collapse respiratory failure ICP monitoring is a double edged sword, and comes with two pretty serious complications – cardiovascular collapse and respiratory failure Organ Retrieval Workshop, Oxford, November 2012

Complications of ICP monitoring Cardiovascular collapse
The perils of maintenance of cerebral perfusion Hypotensive sedative regimens Osmotherapy Hypovolaemia Electrolyte imbalance Vasoconstrictor therapies The problem is that our sedatives are pretty good hypotensive agents, and are particularly potent in patients who are hypovolaemic. WE are then faced with having to correct this with vasoconstrictor agents, which seem regular to lead to subendocardial ischaemia Organ Retrieval Workshop, Oxford, November 2012

Complications of ICP monitoring Respiratory failure
The perils of denial of respiratory cares Deep sedation and paralysis Microaspiration Basal atelectasis Ventilator-acquired pneumonia Mechanical ventilation Bullae Pneumothorax And if it doesn’t get the heart it gets the chest. When you become obsessed about the ICP there is a temptation to avoid anything that causes it to rise – like regular routine chest physio. And of course, because the patient is so deeply sedated – perhaps even paralysed – then they don’t cough anyway, which apparently justifies the policy. Until such time that is that microaspiration past the ET tube leads to dependent atelectasis and VAP Organ Retrieval Workshop, Oxford, November 2012

Systemic inflammation of brain injury
Human and experimental evidence for antigen-independent organ injury from Barklin, Acta Anaes Scand (2009) 53: Organ Retrieval Workshop, Oxford, November 2012

Systemic inflammation of brain death
Before and after brain death Trauma Haemorrhage / massive transfusion Aspiration Hypoxia Hospital acquired infection Mechanical ventilation Trauma and rescue therapies Organ retrieval Sympathetic storm Pulmonary capillary injury Systemic vasoconstriction and organ ischaemia Brain-derived inflammatory mediators Brain death Ischaemia / reperfusion Adapted from Barklin, Acta Anaes Scand (2009) 53: Organ Retrieval Workshop, Oxford, November 2012

Pathophysiology of brain death
Initial observations of ‘le coma dépassé’ Haemodynamic instability Pulmonary oedema Hypothalamic failure Diabetes insipidus Poikilothermia Disseminated intravascular coagulopathy Sometimes our therapies work, and sometimes they do not. We have known for some time – for as long as we have recognised brain death – that the condition has a characteristic pathophysiological profile Haemodynamic instability Pulmonary oedema Hypothalamic failure In particular Organ Retrieval Workshop, Oxford, November 2012

The next few slides show this in action Organ Retrieval Workshop, Oxford, November 2012

Diabetes insipidus And for this patient it started with DI Organ Retrieval Workshop, Oxford, November 2012

Poikilothermia And was soon followed by quite a dramatic fall in body temperature Organ Retrieval Workshop, Oxford, November 2012

Poikilothermia frequently overlooked vasodilatation reduced metabolic rate cool ambient surroundings may contribute to haemodynamic and haemostatic failure will continue until SVR is restored And was soon followed by quite a dramatic fall in body temperature Organ Retrieval Workshop, Oxford, November 2012

Pituitary failure in brain death
Diabetes insipidus ≈ 70% incidence in BSD Failure of neurohypophysis Diuresis of up to 1000 ml / hr Results in hypovolaemia hypokalaemia hypernatraemia May confound diagnosis of death and assessment of perfusion Frequently undertreated The hypothalamus controls the pituitary gland, and miost directly controls the posterior lobe or neurohypophysis. Failure of the posterior lobe results in failure of the secretion of ADH and an inappropriate diuresis that may amount to 1000 ml / hour of ultra-dilute urine. Untreated, it results in Hypovolaemia - hypotension Hypokalaemia – myocardial irritiablity Hypernatraemia – diagnosis of death, liver graft function It is my experience, frequently undertreated Organ Retrieval Workshop, Oxford, November 2012

Pupillary mydriasis The next cardinal event was loss of the pupillary light reflex, which was associated with a temporary period of haemodynamic instability Organ Retrieval Workshop, Oxford, November 2012

Cushing’s reflex Harvey Cushing Neurosurgeon Which was in this case simply a prelude to the final agonal cardiovascular feature of brainstem herniation that we frequently describe as the Cushing reflex – a brief period of hypotension follwoed by an agonal period of hypotension. Organ Retrieval Workshop, Oxford, November 2012

Haemodynamic instability of brain death
Initial observations 80-90% of brain dead donors are haemodynamically unstable Severity α rate of ICP rise Frequently worse in children, young adults Multi-factorial in its aetiology Sympathetic storm and myocardial ischaemia Spinal shock Neurogenic pulmonary oedema Diabetes insipidus Almost always reversible, given sufficient time and effort 80-90% of brain dead donors are haemodynamically unstable Experimentally, it is clear that the severity of the instability is related to speed with which brain death evolves, and that this probably explains why the instability is worse in young people and in very acute pathologies such as acute obstructive hydrocephalus. Various factors potentially contribute to this instability: Organ Retrieval Workshop, Oxford, November 2012

Sympathetic storm Organ Retrieval Workshop, Oxford, November 2012
These slides summarise the haemodynamic changes 1. The sympathetic storm triggers a brief phase of hypertension and tachycardia that may be associated with malignant arrhythmias and myocardial ischaemia Organ Retrieval Workshop, Oxford, November 2012

Transient release of endogenous catecholamines in canine model
Sympathetic storm Transient release of endogenous catecholamines in canine model Contraction band necrosis Experimental models reveal that this is associated with a massive increase in circulating catecholamines, adrenaline, noradrenaline and dopamine And that in some models, but by no means all this is also associated with functional and histological evidence of myocardial injury, the cardinal feature of which is the so-called contraction band necrosis, in which the tissue becomes necrotic in a state of hyper-contraction (in contrast to the necrosis that occurs following myocardial infarction for instance, where the muscle is relaxed) From Novitzky D. Selection and management of cardiac allograft donors. Current opinion in organ transplantation 1998;3:51-61. Organ Retrieval Workshop, Oxford, November 2012

? a form of stress (Takutsubo’s) cardiomyopathy
Sympathetic storm ? a form of stress (Takutsubo’s) cardiomyopathy In its most extreme form, the myocardial injury may represent an example of stress cardiomyopathy or Takutsubo’s cardionmyopathy, in which excessive catecholamine stimulation results in a discoordinated contraction of the ventricle Organ Retrieval Workshop, Oxford, November 2012

Regional neuraxial blockade of sympathetic storm
Haemodynamics of brain death Regional neuraxial blockade of sympathetic storm Also of note, almost all of these immediate changes can be prevented by neural blockade, but not by adrenalectomy, indicating that this is a neurally mediated effect rather than one mediated by catercholamines released from the adrenal medulla. Organ Retrieval Workshop, Oxford, November 2012

Aftermath of the sympathetic storm
Persistent hypotension However the evidence for persisting myocardial injury in brain death is not universal. In this rat model, whilst brain death was associated with the anticipated transient rise in systemic pressure – related to a rise in SVR and fall in cardiac index – this was followed by in effect a hyperdynamic circulation in which ventricular performance was supra normal and associated with normal myocardial histology. From Herijgers et al . The effect of brain death on cardiovascular function in rats. Part I. Is the heart damaged. Cardiovascular Research 38: Organ Retrieval Workshop, Oxford, November 2012

Preserved myocardial performance in rat model of brain death Spinal shock vasoparalysis Hyperdynamic circulation However the evidence for persisting myocardial injury in brain death is not universal. In this rat model, whilst brain death was associated with the anticipated transient rise in systemic pressure – related to a rise in SVR and fall in cardiac index – this was followed by in effect a hyperdynamic circulation in which ventricular performance was supra normal and associated with normal myocardial histology. From Herijgers et al . The effect of brain death on cardiovascular function in rats. Part I. Is the heart damaged. Cardiovascular Research 38: Organ Retrieval Workshop, Oxford, November 2012

Preserved myocardial performance in rat model of brain death and associated with normal myocardial histology. From Herijgers et al . The effect of brain death on cardiovascular function in rats. Part I. Is the heart damaged. Cardiovascular Research 38: Organ Retrieval Workshop, Oxford, November 2012

Brain death related hypotension
This slide summarises then the afterglow of the sympathetic storm – what is left afterwards. The sympathetic storm is transient; if the patient survives this initial phase of hyperstimulation then it is followed by a more prolonged phase of hypotension, the aetiology of which is multi-factorial in part hypovolaemia as a consequence of diabetes insipidus in part because of complete loss of sympathetic tone related to spinal shock and possibly, although the extent of this is variable – both clinically and experimentally - a degree of myocardial injury and ventricular failure Organ Retrieval Workshop, Oxford, November 2012

Afterglow of one big bang
Cosmic microwave background radiation Organ Retrieval Workshop, Oxford, November 2012

Afterglow of autonomic storm Neurogenic pulmonary oedema
Alveolar flooding common frequently misdiagnosed mistreated cardiogenic in origin, non-cardiogenic in behaviour can be florid precursor for systemic inflammatory response Neurogenic pulmonary oedema is the afterglow of the autonomic storm – it is what is left behind when everything else has subsided. It is common – and again, I suspect underdiagnosed and frequently confused with aspiration It is cardiac in origin – it is caused by a massive transient rise in ventricular and pulmonary capillary pressures that quite simply mechanically disrupt the integrity of the pulmonary microcirculation, which is then left very leaky indeed. As a consequence the alveolar flooding can be torrential – both proteinaceous and occasiionally blood stained Organ Retrieval Workshop, Oxford, November 2012

Afterglow of autonomic storm Neurogenic pulmonary oedema
Disruption of the alveolar – capillary barrier common frequently misdiagnosed mistreated cardiogenic in origin, non-cardiogenic in behaviour can be florid precursor for systemic inflammatory response And finally – since the lung is simply a mass of endothelium and epithelium it is this injury that serves as the precursor for any inflammatory response that may subsequently evolve Organ Retrieval Workshop, Oxford, November 2012

Principles of donor management
Fundamental change in priorities once BSD has been diagnosed and the patient identified as a potential donor. Therapies move away from the brain – irrrelevant because it is dead, to donor organ preservation therapies Donor management requires a fundamental shift in focus – from brain to donor organ directed therapies. Organ Retrieval Workshop, Oxford, November 2012

Organ Retrieval Workshop, Oxford, November 2012
Retrospective outcome data from a series of almost 2500 deceased donor kidney grafts indicates that the use of catecholamine infusions in such circumstances is associated with better long term outcomes when compared with those from donors who did not receive catecholamines Organ Retrieval Workshop, Oxford, November 2012

Even though there was no difference in systemic blood pressure between the three groups and even though there was a trend for those donors who received a combination of catecholamine infusion, and whose grafts had the best long term outcome, to have a slightly higher serum creatinine. Organ Retrieval Workshop, Oxford, November 2012

This study also looked at the outcomes of over 700 heart transplants, with the grafts again stratified according to whether the donor received no catecholamine, a single agent or a combination of agents. The study indicated that the patients receiving grafts retrieved from donors on combination therapy were immediately at greater risk of graft failure, and that this effect persisted, and that this effect persisted throughout the life of the grafts Organ Retrieval Workshop, Oxford, November 2012

Hazard ratio 95% CI Nor-epinephrine 1.66 Epinephrine 1.08 Dopamine 1.40 Dobutamine 1.07 Further analysis also indicated that the use of nor-epinephrine was associated with particular poor outcome. Organ Retrieval Workshop, Oxford, November 2012

Catecholamines and donor therapy
The case against catecholamines Catecholamines are raised during the sympathetic storm Catecholamines are implicated in contraction band necrosis Hearts from donors who have received catecholamine infusions do badly (norepinephrine) So there would appear to be an established case against catecholamines, certainly as culprits in causing a problem Little doubt that they are central to the evolution of the sympathetic, and may when severe enough be implicated in the functional changes that are associated histologically with areas of contraction band necrosis, but these changes are by no means inevitable and may be related to severity of the storm There is some retrospective evidence, that hearts from donors who have received catecholamines do rather badly, particularly when norepinephrine has been used Organ Retrieval Workshop, Oxford, November 2012

The case against catecholamines Catecholamines are raised during the sympathetic storm Catecholamines are implicated in contraction band necrosis Hearts from donors who have received catecholamine infusions do badly Therefore we must not give donors catecholamine infusions Hearts may be declined when donors are on high doses of catecholamines And this has led to the view that we must not give any catecholamine to any potential heart donor And that we can expect such donors to be summarily declined by retrieval teams. Organ Retrieval Workshop, Oxford, November 2012

But…… outcomes in kidney transplantation Kidneys from donors who have received catecholamine infusions do well Cardiac injury of the sympathetic storm is reversible Standardised donor management protocols allow retrieval of apparent unsuitable heart grafts Restoration of normovolaemia Correction of vasodilatation Titrated inotropic support However, there is some logical inconsistency in much this argument – of course we would expect hearts that require inotropic support to perhaps fare less well, particularly early on. And then, what of the benefits to be had in terms of improved survival of kidney grafts Organ Retrieval Workshop, Oxford, November 2012

But……. reversibility in survivors of the sympathetic storm Kidneys from donors who have received catecholamine infusions do well Cardiac injury of the sympathetic storm is reversible Standardised donor management protocols allow retrieval of apparent unsuitable heart grafts Restoration of normovolaemia Correction of vasodilatation Titrated inotropic support And then of course, as any of us who have worked in neurocritical care know, the cardiac and respiratory consequences of the sympathetic storm are reversible, given time and adequate support Organ Retrieval Workshop, Oxford, November 2012

But…… transformation of unacceptable donors Kidneys from donors who have received catecholamine infusions do well Cardiac injury of the sympathetic storm is reversible Standardised donor management protocols allow retrieval of apparent unsuitable heart grafts Restoration of normovolaemia Correction of vasodilatation (vasopressin > norepinephrine) Titrated inotropic support (dopamine > epinephrine) Wheeldon et al. Transforming the unacceptable donor. J Heart Lung Transplant ; 14: And then of course, as any of us who have worked in neurocritical care know, the cardiac and respiratory consequences of the sympathetic storm are reversible, given time and adequate support Organ Retrieval Workshop, Oxford, November 2012

Hormone replacement therapy
The case for hormone replacement And this has led to the view that we must not give any catecholamine to any potential heart donor And that we can expect such donors to be summarily declined by retrieval teams. Organ Retrieval Workshop, Oxford, November 2012

Donor optimisation Early observations
Hypotension is bad for kidneys Catecholeamines may be bad for hearts…….. …….. but good for kidneys Hormone replacement may be good for hearts Invasive haemodynamic monitoring may be good for thoracic organs…………if you know how to use it Some ICU clinicians seem reluctant to deliver it Critical care of the potential organ donor is not a passive process and should start as early as possible. Organ Retrieval Workshop, Oxford, November 2012

Donor Care Bundle Organ Retrieval Workshop, Oxford, November 2012

Donor care bundle Key initial priorities
Assess fluid status and correct hypovolaemia Introduce vasopressin infusion and where required introduce flow monitoring Perform lung recruitment manoeuvres (e.g. following apnoea tests, disconnections, deterioration in oxygenation or suctioning) Identify, arrest and reverse effects of diabetes insipidus Administer methylprednisolone (all donors) Organ Retrieval Workshop, Oxford, November 2012

Haemodynamic optimisation I
Objectives Interventions Improve organ perfusion • Correction of hypovolaemia • Restoration of vasomotor tone • Improvement of myocardial contractility Initial therapy a. early correction of hypovolaemia, diabetes insipidus and electrolyte and acid-base disturbances as directed above. b. vasopressin infusion, 1 unit followed by 1 – 4 units / hour: as initial therapy for fluid-unresponsive hypotension, or to replace / reduce existing catecholamine infusions c. Use terlipressin as alternative to vasopressin General haemodynamic goals: • Heart rate 60 – 100 bpm • CVP < 12 cmH2O • Mean arterial pressure 70 mmHg • Systolic blood pressure > 100 mmHg • Mixed venous saturation > 60% Reduction of catecholamine infusion(s) Organ Retrieval Workshop, Oxford, November 2012

Hydroxyethylstarch and post-graft renal function
Choice of colloid Hydroxyethylstarch and post-graft renal function Elohes (MW 200 kDa) Relative lack of free water Osmotic nephropathy Organ Retrieval Workshop, Oxford, November 2012

Hydroxyethylstarch and post-graft renal function
Choice of colloid Hydroxyethylstarch and post-graft renal function It is important to prescribe adequate crystalloid when administering colloid solutions to avoid inducing a hyperoncotic state. Higher molecular weight hydroxyethyl starch (hetastarch and pentastarch MW ≥ 200 kDa) should be avoided in brain-dead kidney donors due to reports of osmotic-nephrosis-like lesions. Organ Retrieval Workshop, Oxford, November 2012

Haemodynamic optimisation II
Objectives Interventions Improve organ perfusion • Correction of hypovolaemia • Restoration of vasomotor tone • Improvement of myocardial contractility Additional therapies in unresponsive cases initiate cardiac output monitoring, titrating fluid, vasoconstrictors or inotropic therapy to following end points: • cardiac index > 2.4 L / min / m2 • pulmonary artery occlusion pressure < 12 cmH2O • systemic vascular resistance 800 – 1200 dynes / sec / cm5 • left ventricular stroke work index > 15 g / kg / minute Use catecholamines as sparingly as possible: dopamine / dobutamine > epinephrine / norepinephrine / phenylephrine. General haemodynamic goals: • Heart rate 60 – 100 bpm • CVP < 12 cmH2O • Mean arterial pressure 70 mmHg • Systolic blood pressure > 100 mmHg • Mixed venous saturation > 60% Reduction of catecholamine infusion(s) Organ Retrieval Workshop, Oxford, November 2012

Haemodynamic optimisation III
Objectives Interventions Improve organ perfusion • Correction of hypovolaemia • Restoration of vasomotor tone • Improvement of myocardial contractility Additional therapies in unresponsive cases b. in refractory cases consider parenteral empirical thyroid replacement therapy • levothyroxine (tetra-iodothyronine, T4), 20 μg IV bolus, followed by 10 μg / hour, or • liothyronine, (tri-iodothyronine, T3 ), 4 μg IV bolus, followed by 3 μg / hour General haemodynamic goals: • Heart rate 60 – 100 bpm • CVP < 12 cmH2O • Mean arterial pressure 70 mmHg • Systolic blood pressure > 100 mmHg • Mixed venous saturation > 60% Reduction of catecholamine infusion(s) Organ Retrieval Workshop, Oxford, November 2012

Haemodynamic optimisation III ? Role for lio-thyronine

Respiratory optimisation
Objectives Interventions Correct atelectasis that follows the apnoea tests Give methylprednisolone, 15 mg / kg. Reinstate routine chest physiotherapy, 2 hourly rotation to lateral position and regular endotracheal suction. 30o head up tilt and firm inflation of endotracheal tube cuff to prevent microaspiration and bronchial soiling Intensive alveolar recruitment - e.g. periodic application of PEEP up to 15 cm H2O, sustained inspiration to 30 cm H2O for seconds and diuresis where indicated. Ventilatory targets are as follows: • Tidal volume 6-8 ml/kg; PEEP 5–10 cmH2O; PIP<30 cmH2O • pH , PaCO2 4.5–6kPa, PaO2>11kPa , SaO2>95% Initiate antibiotic therapy as directed by results of sputum / lavage microscopy and culture, avoiding nephrotoxic anti-microbials. Continue / re-instate general respiratory care of intubated / ventilated patient; protect against microaspiration Identify and reverse specific pulmonary complications of critical care / brain-stem death Introduce lung-protective ventilatory therapies Organ Retrieval Workshop, Oxford, November 2012

Metabolic optimisation
Objectives Interventions Identify and correct the metabolic, biochemical and haematological derangements: • hypernatraemia • hypokalaemia • hyperglycaemia • anaemia • DIC Correct diabetes insipidus and the associated hypovolaemia hypernatraemia Administer parenteral electrolyte supplements to restore serum electrolyte concentrations to normal range. Continue / commence nutrition, and maintain blood glucose 4 – 10 mmol / L with iv insulin Maintain haemoglobin at 9 – 10 g / dl Treat derangements in coagulation with appropriate clotting factors and / or platelets if there is significant on-going bleeding. Have clotting factors available for organ retrieval. Normalise markers of adequate perfusion: decreasing blood lactate, mixed venous saturation > 60% urine output of 1 – 2 ml/ kg/ hour (in absence of diabetes insipidus). Organ Retrieval Workshop, Oxford, November 2012

Duration of support following diagnosis of brain death
heart liver kidney pancreas lungs small bowel Time after diagnosis of brain death (hours) Inaba et al. J TRAUMA : Organ Retrieval Workshop, Oxford, November 2012

UK donation and transplantation, 2012

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