UK donation and transplantation, 2012

Organ Retrieval Workshop, Oxford, November 2012

UK donation and transplantation, 2012

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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

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Failure to maximise the gift of donation dishonours both donors

and their families


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Heart transplant rates, 2010

If the vision is ‘every organ, every time’, the reality is that ‘we lose

more than we use’


Phases of graft injury


Pre-retrieval graft injury


Organ damage in the DBD donor

Causes of organ impairment

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

The brain dead organ donor has a distinct collection of

acute physiological disturbances that are

almost always correctable

Fatty kidney from an obese hypertensive donor


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% Donor cause of death

Cause of death in UK DBD donors


Ages of deceased donors in the UK, 2001-11


BMI of deceased donors in UK, 2001-11


Effect of donor age on organ retrieval in UK

2.562.73 2.72

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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) Brain-directed therapies take precedence over systemic support


Principles of brain resuscitationICP monitoring

The real complications of ICP

monitoring

• cardiovascular collapse

• respiratory failure


Complications of ICP monitoringCardiovascular collapse

The perils of maintenance of

cerebral perfusion

• Hypotensive sedative

regimens

• Osmotherapy− Hypovolaemia

− Electrolyte imbalance

• Vasoconstrictor therapies


Complications of ICP monitoringRespiratory failure

The perils of denial of

respiratory cares

• Deep sedation and paralysis

• Microaspiration

− Basal atelectasis

− Ventilator-acquired pneumonia

• Mechanical ventilation

− Bullae

− Pneumothorax


Systemic inflammation of brain injury

from Barklin, Acta Anaes Scand (2009) 53: 425-35 Human and experimental evidence for antigen-independent organ injury


Systemic inflammation of brain deathBefore and after brain death

Trauma

Haemorrhage / massive transfusion

Aspiration

Hypoxia

Hospital acquired infection

Mechanical ventilationTrauma and rescue therapies

Organretrieval

Sympathetic storm

Pulmonary capillary injury

Systemic vasoconstriction and organ ischaemia

Brain-derived inflammatory mediators

Braindeath

Ischaemia /reperfusion

Adapted from Barklin, Acta Anaes Scand (2009) 53: 425-35



Initial observations of ‘le coma

dépassé’

• Haemodynamic instability

• Pulmonary oedema

• Hypothalamic failure

− Diabetes insipidus

− Poikilothermia

• Disseminated intravascular

coagulopathy




Pathophysiology of brain deathDiabetes insipidus


Pathophysiology of brain deathPoikilothermia


Pathophysiology of brain deathPoikilothermia

• frequently overlooked

• vasodilatation

• reduced metabolic rate

• cool ambient surroundings

• may contribute to haemodynamic

and haemostatic failure

• will continue until SVR is restored


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


Pathophysiology of brain deathPupillary mydriasis


Pathophysiology of brain deathCushing’s reflex

Harvey CushingNeurosurgeon


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

Haemodynamic instability of brain death


Sympathetic storm


Sympathetic storm

Transient release of endogenous catecholamines in canine model

From Novitzky D. Selection and management of cardiac allograft donors. Current opinion in organ transplantation 1998;3:51-61.

Contraction band necrosis


Sympathetic storm

? a form of stress (Takutsubo’s) cardiomyopathy


Haemodynamics of brain death

Regional neuraxial blockade of sympathetic storm


Aftermath of the sympathetic storm

Persistent hypotension

From Herijgers et al . The effect of brain death on cardiovascular function in rats. Part I. Is the heart damaged. Cardiovascular Research 38: 98-106



Preserved myocardial performance in rat model of brain death


Spinal shockvasoparalysis

Hyperdynamiccirculation



Preserved myocardial performance in rat model of brain death



Brain death related hypotension


Afterglow of one big bang

Cosmic microwave background radiation


Afterglow of autonomic stormNeurogenic pulmonary oedema

Alveolar flooding

• common

• frequently

− misdiagnosed

− mistreated

• cardiogenic in origin, non-

cardiogenic in behaviour

• can be florid

• precursor for systemic

inflammatory response


Afterglow of autonomic stormNeurogenic 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


Principles of donor management

Donor management requires a fundamental shift in focus – from brain to donor organ directed therapies.





Hazard ratio

95% CI

Nor-epinephrine 1.66 1.14-2.43

Epinephrine 1.08 0.61-1.90

Dopamine 1.40 0.89-2.20

Dobutamine 1.07 0.77-1.51


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)


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



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



But……. reversibility in survivors of the sympathetic storm




• 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





• 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. 1995; 14: 734-742

But…… transformation of unacceptable donors


The case for hormone replacement

Hormone replacement therapy


• 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

Donor optimisationEarly observations

Critical care of the potential organ donor is not a passive process and should start as early as possible.


Donor Care Bundle


Donor care bundleKey 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)


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)


Choice of colloidHydroxyethylstarch and post-graft renal function

• Elohes (MW 200 kDa)

• Relative lack of free water

• Osmotic nephropathy


Choice of colloidHydroxyethylstarch 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.


Haemodynamic optimisation II






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.



• CVP < 12 cmH2O






Haemodynamic optimisation III






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



• CVP < 12 cmH2O






Haemodynamic optimisation III? Role for lio-thyronine


Respiratory optimisation


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 30 - 60

seconds and diuresis where indicated. Ventilatory targets are as follows:• Tidal volume 6-8 ml/kg; PEEP 5–10 cmH2O; PIP<30 cmH2O

• pH 7.35- .45, 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


Metabolic optimisation


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).


heart

liverkidney

pancreas

lungs

small bowel

Time after diagnosis of brain death (hours)

Duration of support following diagnosis of brain death

Inaba et al. J TRAUMA 2010 68:

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UK donation and transplantation, 2012