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M INISTRY OF EDUCATION AND TRAINING M INISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES DAO THI KIM DUNG RESEARCH OF RESUSCITATION EFFECTS TO ORGAN FUNCT

M INISTRY OF EDUCATION AND TRAINING M INISTRY OF DEFENCE

108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

DAO THI KIM DUNG

RESEARCH OF RESUSCITATION EFFECTS TO ORGAN FUNCTIONS IN BRAIN - DEAD POTENTIAL

THIS WORK WAS COMPLETED AT 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

The thesis can be founded at:

1 Vietnam National Library

2 Library of 108 Institute of Clinica l Medica l and Pharmaceutical Sciences

3 Library of Viet Duc University Hospital

INTRODUCTION

1 The neccessary of the subject

Organ transplantation is the last -line treatment for patients with end-stage organ failure which can help the patient to have a new life All over the world, the major problem is the shortage of donated organes, numbers of donated organs only meet less than 10% of the demand

In Vietnam, the current estimate of all kinds organ donors only meets 5% of transplant needs In July 1st 2007, Vietnamese parliament has officially issued the “Law on donation, tissue and organ transplants, donating the cadaver" No.75/2006/QH11

Number of living donors is limited, therefore the main source of organ transplantation is now cadaveric donors But in reality, using organs from cadaveric donors still has a lot of difficulties Nearly all

of brain death patients suffer from organ failures and many of them have multiple organ failures Unadequate resuscitation can limite one organ’s quality or even affect the whole body Another way, resuscitation of an organ can negatively affect another organ This process reduces the number of organs which can be used in transplantation

There are already some studies in Vietnam whose aims is providing the protections for single organs, so in this study, we would like to study a strategy of multiple organ resuscitation in the purpose that we can maximize the number of organs which can be donnated

So, we performed the study "Research of res uscitation effects

on organ functions in brain-dead potential donors" with 2

functions of some organs in brain-dead potential donors

2 The main ne w scie ntific contributions of the thesis

The thesis is the first study which evaluates the results of formultiple organs resuscitation strategy in brain death potential donors From the results of this study, it is recommended to optimize the hemodynamics to adequately perfusion of organs after brain death

to ensure the functions of the transplanted organs later;the organs should be used in the 24 first hours frombeginning of organ resuscitation (about 12 hours after the declaring of Brain-dead diagnosis Council) because the organ functionsare is the best

3 Structure of the thesis

The thesisconsists of 129 pages (introduction 2 pages, overview

37 pages, subjects and methods 25 pages, results 30 pages, dicussion

32 pages, conclusion 2 pages, and recommendation 1 page; with 37 tables, 23 images, 17 graphs and 1 figure The thesis also used 160 references, 18 refs in Vietnamsese and 142 refs in English

CHAPTER 1 OVERVIEW

1.1 Summary of anatomical and physiological characte ristics of the organs re late d to brain de ath

1.1.1 Summary of characteristics of the CNS related to brain death 1.1.2 Summary of characteristics of the organs related to brain death

1.1.3 Pathophysiology and complications of brain death

1.1.3.1 Pathophysiology of brain death: Changes of cardiovascular;

Changes in hepatic and coagulated function; Changes of neurology; Changes of hormone; Activating of inflammatory response; Increasing

of cytokine after brain death; Endothelin axis; Effecting on the

nervous - muscle system; Hypothermia

1.1.3.2 Complications after brain death: unstable hemodynamics,

hypoxia, lack of circulation, increased blood osmotic pressure,

hyperglycemia, hypothermia, coagulopathy

1.1.3.3 Electrolyte disorders after brain death: hypernatremia,

hypokalemia, hypoglycemia, hypocalcaemia, hypophosphatemia

1.2 Several domestic and foreign studies on clinical and laboratory characte ristics in brain-dead potential donors

1.2.1 Brain death and brain death diagnosis in the world and in Vietnam

1.2.1.1 Definition: Brain death is defined as an “Irreversible cessation

of all functions of the entire brain, including the brainstem”

1.2.1.2 History

In 1959, Mollaret - Goudon (France): mentioned "coma" In 1995, the American Academy of Neurology (AAN) guideline: defined as coma, absence of brainstem reflexes and apnoea - updated in 2010: A patient determined to be brain dead is legally and c linical dead

1.2.1.3 The diagnostic criteria of brain death in the world

UK (1976), France (1996), USA (1995) - updated (2010)

1.2.1.4 Criteria of brain death diagnosis of Vietnam

According to the "Law on donation, tissue and organ transplants, donating the cadaver"and the Ministry of Health’s instruction

"Clinical and subclinical standards and cases of non-application of clinical criteria to determine brain death"

1.2.2 Several studies on clinical and laboratory characteristics

1.2.2.1 In the world: brain-dead patients have disorders such as

hypotension, coagulation disorders, diabetes mellitus, acidosis, kidney failure, acute respiratory fa ilure, the cause of brain death is stroke and

head trauma

1.2.2.2 In Vietnam: the authors have found a decrease in body

temperature and diabetes mellitus, organ functions deteriorated after

36 hours of brain death The main cause is head trauma due to traffic accidents

1.3 Several domes tic and fore ign studies on res uscitation and mainte nance of brain dead donors

1.3.1 Resuscitation measures

- Cardiovascular resuscitation: the adult hemodynamic targets in brain dead potential donors, Law 100, Physiological target for cardiac or cardio-pulmonary donation, Principles for resuscitation of cardiac donors

- Endocrine: treatment of hormonal disorders after brain death

- Respiratory resuscitation: protectingpulmonary ventilation

- Renal resuscitation: compensate for volume, MAP >60 mmHg

- Hematologic resuscitation: maintain Hb ≥ 8 g/dl

- Temperature resuscitation: maintaining body temperature 36 - 3705

1.3.2 Guidelines for resuscitation of different centers in the world

- Pittsburgh Medical Univers ity and University of Houston Medical (Texas) (2004)

- According to the Swiss Association (2006)

- Guidelines of the Australian Transplant Association (2008)

-The latest guide of New South Wales (Australia) on resuscitation of brain dead potential donors (2016)

1.3.3 Take care of the brain dead potential donors: forensic

problems, cultural aspects, communication skills: basic skills should

be trained

1.3.4 Several domestic and foreign studies on resuscitation and maintenance of brain dead donors

1.3.4.1 Several foreign studies on resuscitation and maintenance of brain-dead donors: No matter which donor’s organ resuscitation, the

resuscitation of hemodynamic (cardiovascular) and respiratory (pulmonary) are still the decisive factors to enhance visceral perfusion, increase oxygen for tissues and organstoprotect donors’s organ functions

1.3.4.2 Several domestic studies on resuscitation of brain-dead donors: author Nguyen Viet Quang, Mai Xuan Hien and Vu Minh

Duong found the high cardiac arrest rates at 12, 24, 36 hours after brain death, while Nguyen Quoc Kinh, Do Tat Cuong found the high rate in the period of 36 - 48 hours

1.3.5 The current situation of organ donation in the world and in Vietnam

1.2.1 The current situation of organ donation in the world

In 1954, J Murray performed the 1st kidney transplant from a living donor (twin) In 1962, Murray successfully performed the 1stkidney transplant from a brain-dead donor Southeast Asia marked the

1sttransplants: Hongkong 1969 (kidney), Thailand 1987 (liver, heart)

1.2.2 The current situation of organ donation in Vietnam

In Vietnam, the 1st kidney transplant from living donor in 1992 and the 1storgan transplants from brain-dead donor in 2010 According

to the National Organ Coordination Center, the number of transplants from brain dead donors are 217 cases (6.4%)

CHAPTER 2 - SUBJECTS AND METHODS 2.1 Subjects

2.1.1 Location and time of the study: In Center of Anesthesia and

Surgical intenssive care from 01-12/2015 at Vietduc U Hospital

2.1.2 Criteria of patients in to study

- Subjects: 47 severe head trauma patients with 3-point Glasgow,

eligible for admission to the ICU for diagnosis and resuscitation of brain death, to carry out the diagnosis of brain death according to Vietnamese law standards Determined as a potential donor The family agreed to realize the diagnostic test of brain death and resuscitation

- Exclusion criterias: Head trauma with severe thoracic-abdominal

trauma Multi-organ fa ilure before determining brain death History of chronic liver, kidney, cardiovascular, respiratorydiseases, endocrine disease, systemic infection, drug addictions, HIV, hepatitis (B,C), viral encephalitis, and progressive tuberculosis Ultrasound screening detecting kidney, liver, and heart disease Brain tumors (malignant)

- Criteria to take the patient out of research: The patient's family

didn’t agree to diagnose and resuscitateof brain death The patient died before havingexmination of the organ functions Patients were not diagnosed with brain death according to Vietnamese law standards Patients werenot treated correctly according to the regiment

2.2 Methods

2.2.1 Design of study: Prospective, description, comparison before -

after study (intervention of goal resuscitation)

2.2.2 Sample size: applying the sample size formula to the

before-after studies N = 47

2.2.3 Drugs and facilities

- Drugs: infusion liquids, blood products, cathecolamine, endocrine

- Facilities: Monitoring, ventilator, blood-air test, PiCCO monitoring

2.2.4 The content of Research

2.2.4.1 The stages of research: T0: Background time (1st clinical

diagnosis of brain death); T1: After 12 hours: 3rd brain dead diagnose brain death 3 times (determined - conclusions); T2: After 24 hours of resuscitation of brain death (organ resuscitation); T3: After 36 hours

of diagnosis and resuscitation of brain death; T4: After 48 hours of diagnosis and resuscitation of brain; Tm: Time before harvesting organs

2.2.4.2 Criterias for evaluating

a General characteristics of patients Criteria for evaluating general

characteristics of patients:

- Anthropometric characteristics of the brain dead potential donors

+ Causes of brain death, brain damage

+The need for using inotrops, vasopressine in the whole process + Patient outcome after brain-dead resuscitation

b Study of clinica l and laboratory characteristics in brain dead potential donors: We recorded the number of patients at the time T0 had the following clinical and laboratory indicators: The incidence of organ dysfunction in 47 potential brain deaths; Functions of cardiovascular; respiratory; kidney; liver and hematology; Fluid - endocrine and body temperature SOFA: Total SOFA, individual SOFA, number of patients with multiple organ failure

c Evaluate the effects of resuscitation measures on the functions of some organ in brain-dead potential donors

- Results of hormone replacement therapy: The rate of increased/decreased T3, T4, TSH, cortisol before and after treatment

- We recorded the number of patients at different times (T0, T1, T2, T3, T4, Tm) with the following changes in indicators:

+The demands of cathecolamine; the demands for the kind of cathecolamine/ each patient; cathecolamine dose (Noradrenaline, Adrenaline, Dobutamine, Dopamine)

+The changes of basic hemodynamic through heart rate, MAP, CVP; the number of patients with decreased MAP< 70 mmHg, hypothermia

≤ 350C and diabetes insipidus

+ The changes of SOFA scores; of lactat; of prothrombin rate; of

plate let number

+ The changes of respiratory and acidosis through parameters PaCO2, PaO2, PaO2 / FiO2; The changes of hepatic functions through blood glucose parameters, SGOT, SGPT, direct bilirubin; The changes of renal functions through blood ure, blood creatinine, urine output and

dopamine dose

+ Resuscitation results according to the target "rule 100", target "rule

100 *" amended through parameters maxBP, Hb, PaO2, urine output, Number of eligible patients

+ Evolution of PiCCo invasive hemodynamic parameters through parameters CI, SVRI, GEDI and ELWI; Resuscitation results according to PiCCo instructions: CI ≥ 3 ml/min/m2, GEDI ≥ 680 ml/m2, ELWI ≤ 10%, the number of patients meeting the criteria of 3 PiCCo parameters

- We record the number of patients after treatment by destination w ith the following indicators:

+ Cardiac arrest group vs or organ donation outcome in patients

+ Number of organs eligible for transplant after resuscitation of 47 patients with brain death; number of organs eligible for transplant among resuscitated patients; organ transplantation results from a group of 47 patients with brain death considering organ donation; Transplant rate from 47 patients with brain death

+ The percentage of organ transplants from 25 organ donors; Average number of days hospitalized after a transplant

2.2.5 Method to proceed

2.2.3.1 Step 1: Receive head trauma patients and install monitoring

2.2.3.2.Step2: Thyroid hormone (T3,T4,TSH), Troponin T, cortisol;

SVO2/SCVO2, blood-gas test, blood cell test, biochemistry test, coagulation test, urine test, SOFA score every 12 hours

2.2.3.3 Step 3: Intensive resuscitation

Table 2.1 The targets of resuscitation

Re suscitation measures Targets

Law 100* Sys tolic blood pressure ≥ 100, Urine output ≥

100 ml/hour, PaO2 ≥ 100 mmHg , Hb ≥ 80 g/L

PiCCo hemodynamic

regimen

CI ≥ 3 ml/ min/ m2 GEDI ≥ 680 ml/ m2 ELWI ≤ 10 %

Lung protected

ventilation

Donation: PaO2/FiO2> 300; FiO2 ≤ 0.5

No donation: PaO2>70 mmHg; SaO2> 88%

Hormone replacement

therapy

Levothyrox (belthyro x) 2,5 mcg/kg/24h Methylpresnisolon 15 mg/kg IV Maintain blood glucos e 4-9 mmo l/l

Treatment of diabetes

mellitus

Maintain Na + ≤ 155 mmol/L Maintain the volume o f urine 1-2 ml/kg/hour

Maintain body

temperature 36 - 3705

2.2.6 Criteria and definitions used in research

2.2.7 Data analysis: SPSS 16.0 for Window

2.2.8 Ethics in research

The research is a branch in the State-level project, which is approved by the Vietnam-Germany Professional and Ethical Council

as well as by the Ministry of Science and Technology In the process

of implementing the research, we strictly adhere to the law on organ transplants of the National Assembly, regulations of the Ministry of Health Resuscitation process has been approved by Vietduc Hospital

CHAPTER 3 - RESULTS 3.1 Ge ne ral characte ristics

3.1 Ge ne ral characte ristics of research patie nts

3.1.1 Anthropometric characteristics

Table 3.1 Age characteristics of brain death patients in the study

Comments: The average age is 32.91 ± 12.08 years old

Chart 3.1 Gender distribution of patients in the study Comments:

men account for 85.1% and females account for 14.9%

Table 3.2 Characteristics of we ight and BMI of patients in the study

Comments: Average weight and BMI are suitable for VNese people 3.1.2 Characteristics of injuries in brain-dead patients in the study

Table 3.3 Characteristics of crania l injuries of patients in the study

Comments: 17% of multiple injuries, 83% of head trauma alone

Intracranial hematoma, brain suppression, subarachnoid hemorrhage

accounted for 76.6%

3.1.3 Characteristics of cathecolamins use during resuscitation

Table 3.4 Demands for cathecolamins in whole resuscitation process

Comments: The number of patients are treated noradrenalin accounted

for the highest of 95.7%

3.1.4 The outcome of the patients in the study

Chart 3.2 The patient's outcome after resuscitation Comments:

100% death (46.8% biological death and 53.2% organ donation after

Comments: The average of urine output and blood osmolarity pressure

in group with diabetes is significantly higher than the other

Table 3.6 The incidences of cardiac and pulmonary function index

disorders before organ resuscitations

Comments: 21.3% of patients havehypotension <70 mmHg, 33% of

patients had PaO2/FiO2 reduction <300 and 21.3% of patients have ELWI> 10

Table 3.7 The incidences of renal, hepatic and hematological

function disorders before organ resuscitations

Organ Data Unit Criteria No.(n) Ratio

Creatinine/plasma mmo l/ l > 110 8 17,1