Cardiac Arrest and Its Neurological Effects and Use of Mild Hypothermia to Improve Neurological Outcomes - Case Study Example

CARDIAC ARREST AND ITS NEUROLOGICAL EFFECTS USE OF MILD HYPOTHERMIA TO IMPROVE NEUROLOGICAL OUTCOMES Introduction Cardiac arrest is defined as the seizure of heart activity due to physiological or pathological causes which needs immediate therapeutic intervention. It is the terminal event in any fatal disorder. (Merck Manual). It is diagnosed by the failure to detect an effective mechanical heartbeat. This can occur due to many reasons, the prominent ones being ventricular tachycardia, ventricular fibrillation or cardiac asystole. When cardiac arrest occurs, the heart cannot beat effectively, the brain no longer receives the blood it needs to function and the person loses consciousness immediately. It is usually the sequel to undiagnosed coronary artery disease. Cardiac arrest can start with a fast ventricular tachycardia and degenerate into ventricular fibrillation. Recovery from cardiac arrest is possible only if the heartbeat and circulation is restored by cardiac massage within a few minutes of its occurrence. It is often fatal when the patient is unattended or alone. Cardiopulmonary resuscitation (CPR) is indicated immediately before the patient reaches the hospital where defibrillation can be carried out. Etiology Cardiac arrest occurs in adults mostly due to pre existing cardiac disease, especially coronary artery disease. Other reasons which can trigger a cardiac arrest are circulatory shock due to trauma, drug overdose or toxicity, pulmonary embolism and other metabolic disturbances. (Merck Manual) In younger people and children the causes can vary from trauma to toxicity, pulmonary infection and obstruction and sudden infant death syndrome. The causes of cardiac arrest have been tabulated by Birt David et al (1999) as follows: Table 1 Causes of cardiac Arrest Cardiac Diseases Respiratory Causes Ischemic Heart Disease Hypoxia (ususlly causes asystole) Acute Circulatory Obstruction Hypercapnia Fixed Output States Metabolic Changes Cardiomyopathies Potassium Disturbances Myocarditis Acute Hypercalcaemia Trauma and Tamponade Circulating Catecholamines Direct Myocardial Stimulation Hypothermia Circulatory Causes Drug Effects Hypovolaemia Direct Pharmacological Actions Tension Pneumothorax Secondary Effects of drugs Air or Pulmonary Embolism Miscellaneous Causes Vagal Reflex Mechanisms Electrocution Drowning Hypoxia is inadequate oxygenation to the tissues in the body while Hypercapnia is the presence of abnormally high level of carbon dioxide in the circulating blood. Cardiomyopathies are miscellaneous pathological conditions of the heart muscle while Myocarditis is the inflammation of the cardiac muscles. Tension Pneumothorax is a condition in which there is abnormal pressure in the thoracic cavity due to pathological condition of the collapsed lungs. Abnormal Vagal reflex mechanisms also alter the heartbeat and emboli precipitate cardiomyopathies. Circulating catecholamines like Epinephrine, Dopamine and Norepinephrine have a profound effect on the functioning of the heart. Metabolic changes affecting the Calcium and Potassium levels disturb the normal homeostasis mechanisms of the body and these ions have important roles in the functioning of the heart muscle. Drugs used for treatment or otherwise also have miscellaneous effects on cardiac rhythm and functioning. Pathophysiology of Post CPR Period Cardiac arrest is a grave medical emergency and can lead to neurological changes due to the anoxia suffered by brain. Even if the transportation of the patient to an intensive care facility after receiving CPR is rapid neuronal damage can manifest during this short interval. Short periods of cerebral ischemia can lead to irreversible death of neurons. (Schneider A. et al, 2006). The neuronal damage occurs in two stages. In the first stage, neuronal death takes place due to oxygen deprivation. In the second stage, when circulation has been restored by emergency medical interventions, there is a period of apoptotic degeneration of neurons, promoted by several mediators, in the vulnerable areas of the brain, which is a cell suicide mechanism that enables the patients’ defensive mechanism to eliminate cells which threaten survival. The neuronal damage is the primary reason for deaths in cardiac arrest patients in 70% of the cases (Schneider A. et al, 2006). Besides the neuronal damage, the typical sequence following cardiac arrest is myocardial dysfunction i.e. the malfunctioning of heart muscle, generalized systemic inflammation and activation of coagulation of blood. Ischemia due to cardiac arrest leads to direct cellular damage and edema formation. Edema is very harmful in the brain as there is no room for expansion inside the skull. The increase in intracranial pressure leads to decrease in cerebral perfusion post resuscitation. (Merck Manual). At the cellular level, there is decreases ATP production (Adenosine tri phosphate) which leads to loss of membrane integrity. As a result there is efflux of K and influx of Na and Ca ions. Excess intracellular Na leads to production of oedema and excess Ca damages the mitochondria further decreasing the production of ATP. There is increase in nitric oxide production which leads to the formation of free radicals which damage the cells. In the neurons the excessive ionic flux leads to depolarization leading to release of the present neurotransmitters, especially glutamate which worsens the intracellular Ca overload. (Merck Manual). According to Birt David, et al (1999), after a brief period of cardiac arrest the partial pressure of oxygen in the blood PaO2 falls dramatically due to hypoxia and consumption of oxygen, which is particularly high in the brain (4 milliliters per minute). There is progressive accumulation of carbon dioxide. The PaO2 in brain falls from 13kPa to 2.5kPa within 15 seconds lading to unconsciousness. The PaO2 level is zero after the elapse of 60 seconds. Under normal conditions both the brain and heart have a relatively high rate of oxygen consumption and oxygen delivery to both these organs falls to critical level during cardiac arrest. If ventricular fibrillation is the precipitating cause, myocardial metabolism goes on at its normal rate which exhausts both oxygen and high energy phosphate supplies. Acidosis ensues due to accumulation of carbon dioxide and increased anaerobic metabolism. Role of Hypothermia as a Therapeutic Measure in Cardiac Arrest Hypothermia is a state of body temperature below normal in a homoeothermic organism. In contrast to accidental hypothermia, hypothermia used, for example, with cardiopulmonary bypass, neurosurgery, or cardiac arrest is administered in a controlled way. Hypothermia is graded into 4 levels (Hitchcock C et al, 1962): mild (34°C to 36°C), moderate (28°C to 33°C), deep (17°C to 27°C), and profound (4°C to 16°C) (Reuler J.B., 1978) In the early 1990s, a series of animal experiments proved that mild hypothermia induced after return of spontaneous circulation and maintained for several hours dramatically reduced the severity of anoxic neuronal injury. (Bernard S.A., 2005). This generated interest in this field and a number of animal studies and trials were undertaken. In the mid 1990s it was found that it was feasible to use hypothermia in human patients and it did not have any detrimental effect on the patient. Dramatic improvement in neurological and other outcomes in people who suffered cardiac arrest was seen in the subsequent controlled trials. On the basis of positive results all over the world, the International Liaison Committee on Resuscitation endorsed mild hypothermia as a recommended treatment for patients suffering from cardiac arrest with an initial cardiac rhythm of ventricular fibrillation in 2003. The success by using hypothermia as a therapeutic intervention in cardiac arrest and increasing success from all over the world triggered more clinical trials and studies with identical results. Case Studies 1. One of the most cited studies on the subject is from ‘The New England Journal of Medicine’ (N Engl J Med, Vol. 346, No. 8, February 21, 2002). In this study, the effect of mild systemic hypothermia on neuronal recovery in patients who had survived cardiac arrest due to ventricular fibrillation was seen in a multicenter trial. 55% of the group which was subjected to hypothermia showed significant neuronal recovery while in the normothermic group who received traditional treatment; this figure was only 39%. Mortality figures were also significantly less in the hypothermic group. Patients for this study were selected meticulously in order to eliminate variations due to other interfering factors such as pre existing coagulopathy, history of terminal illness prior to cardiac arrest, participation in other trials, pregnancy, prior administration of drugs, etc. The study was designed as a randomized, controlled trial with blinded assessment of the outcome. Hypothermia was induced by a device which cooled the mattress of the patient, whose temperature was monitored using a bladder probe as well as an infra red device to monitor initial temperature from the tympanic membrane. The target temperature of 32-34°C was maintained for 24 hours from the start of cooling and aided with ice packs if there was any deficiency. This was followed by a passive rewarming period of eight hours. Recommended guidelines for uniform reporting of data were followed. Laboratory tests for evaluating the patients were carried out at the baseline, and then at 12 and 48 hours after the occurrence of the cardiac arrest. The outcome criteria used was the ‘Pittsburgh cerebral performance standards’ in which category I is considered as ‘good recovery’, category II as ‘moderate disability’, category III as ‘severe disability’, category IV as ‘a vegetative state’ and category V as ‘death’. There were secondary end points used in the study which were mortality at six months after the initiation of the trial and the rate of complications during the first seven days following cardiac arrest. The paper states that experimentation with hypothermia was conducted as early as the 1950-60s, but the results obtained then were inconclusive as well as the temperature to which the body was cooled was lower. The conclusion of the study was that the patients who were subjected to hypothermia had a favorable neurological outcome as compared to the normothermic group. The study however reports that sepsis was more likely to develop in the hypothermic group as compared to the normothermic one. Overall, the benefits of hypothermia were found to be more than the adverse effect of infection. Another lacuna pointed out by the authors is their failure to make the study double blind as the attending physician could not be blinded to the choice of the two groups. However this lack of blinding did not have any effect on the results obtained. 2. Another original investigation explored the effects of hyperthermia after cardiac arrest and concluded that it was associated with an unfavorable neurological outcome (Zeiner Andrea, et al, 2001). The objective of this study was to evaluate the impact of body temperature on neurological outcome after cardiopulmonary resuscitation. The study was conducted at a tertiary care university hospital with an overall span of three and a half years. Interestingly, in this study no therapeutic procedure to produce hypothermia was used, rather it aimed at analyzing the effect of hyperthermia on patients who had suffered a cardiac arrest. The method used was to monitor the body temperature of patients who had suffered from a witnessed cardiac arrest with presumed cause from cardiac origin. Temperature was recorded at the time of admission to the emergency department and thereafter at 2, 4, 6, 12, 24, 36 and 48 hours. The temperature immediately on admission was monitored with infrared tympanic thermometry and thereafter by pulmonary artery catheterization. The lowest temperature recorded within the first four hours, and the highest temperature attained during the first 48 hours after restoration of spontaneous circulation was correlated to the best achieved cerebral performance categories (CPCs). Cerebral Performance Categories were determined using a known standard procedure called the ‘Glasgow overall performance categories. Basically these were defined as follows: a) CPC 1: Conscious and alert with normal function or only slight disability. b) CPC 2: Conscious and alert with moderate disability. c) CPC 3: Conscious with severe disability. d) CPC 4: Comatose or in persistent vegetative state. e) CPC 5: Brain Death. The interval from collapse to first basic and/or advanced life support was defined as no-flow duration, and the interval from the beginning of life support until the return of spontaneous circulation was defined as low-flow duration. Standard statistical design appropriate for this study was used. The authors concluded that hyperthermia, which they elaborated as a value higher than the threshold value of 37° C was associated with an unfavorable functional neurological recovery. Each degree Celsius above 37° C showed an increase in producing severe disability, coma or a persistent vegetative state (CPC 3-4). The reasons for hypothermia were postulated to be infection and pulmonary aspiration due to comatose state. Patients with an unfavorable functional neurological recovery showed a decrease of temperature within the first 4 hours after restoration of spontaneous circulation; compared with patients with a good functional neurological recovery, they had significantly lower temperatures. Patients with an unfavorable functional neurological recovery had a significantly higher highest temperature observed and weighted mean temperature within 48 hours after restoration of spontaneous circulation. 3. Another study (Bernard S.A., 1997) on the use of therapeutic hypothermia in patients who had suffered cardiac arrest was carried out at four participating Australian centers where 77 randomized patients who had been resuscitated but were in comatose state were subjected to hypothermia by the use of ice packs to a target temperature of 33° C. This target temperature was attained within two hours of the return of spontaneous circulation and maintained for twelve hours. The patients were then actively re warmed to the normal body temperature. The primary endpoint of the study was the survival of the patients to the stage where they could be discharged from the hospital with sufficient neurological functioning. 49% of the patients treated with this regimen of hypothermia were discharged with appreciable recovery in neurological function as compared to the other group (not subjected to hypothermia) in whom the figure of discharged patients was only 26%. The study has since then been extensively reviewed by the authors and found to be duplicable and substantiated by further research in this area. The author has recommended rapid infusion of a large volume (40mL/Kg) of ice cold intra venous fluid to induce hypothermia in patients who have suffered cardiac arrest. He has also described the newer automated surface cooling/warming devices which have recently been developed and allow tight control of body temperature of the patients in Intensive Care Units (ICUs). (Bernard S A, 2005). 4. In one of the latest studies, Skulec R. et al (2008) have studied the effects of inducing mild hypothermia in cardiac arrest survivors presenting with cardiogenic shock syndrome. The authors have investigated the benefits and risks of using mild hypothermia in patients who remain in cardiogenic shock after the return of spontaneous circulation. Cardiac arrest survivors who were treated with mild hypothermia were analyzed in the ICCU (Intensive Coronary Care Unit) and a comparison study was conducted between those patients with cardiogenic shock syndrome and the ones who were circulatory stable. A total of 56 patients with 28 in each group were chosen for this study. In-hospital mortality in cardiac arrest survivors treated with mild hypothermia was found to be higher in patients with cardiogenic shock than in stable patients in this study, while the neurological outcome was comparable in both the groups. Therefore it was concluded that induction of mild hypothermia should be considered in cardiac arrest survivors with cardiogenic shock syndrome who demonstrated spontaneous return of circulation. Review of Literature Invariably, all research done till date has pointed out clearly, the benefits of inducing hypothermia in cardiac arrest patients where the etiology is of cardiogenic origin i.e. Ventricular fibrillation and the increased neuronal survivability due to the procedure. The indicators to develop this kind of therapeutic intervention were stimulated by the interesting animal studies carried out as early as 1950 when Bigelow WG et al demonstrated that there was a possible role of hypothermia during cardiac surgery in dogs where maintaining a low temperature was found to have some beneficial effect. Animal experiments showed that therapeutic mild hypothermia improved outcome after global cerebral ischemia in different animal species. Vigorous experimentation on animals in the early 1990s established the beneficial effects of hypothermia without doubt. Leonov Y et al, 1990, found that mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. This was substantiated in another dog experiment carried out by Sterz F. et al in 1991. Kuboyama K. et al, 1993 conducted a study on dogs where they established the importance of immediate cooling after cardiac arrest as delay negated the beneficial effects of mild resuscitative hypothermia. Similar studies were carried out in other animals as well. Colbourne & Corbett, et al found that delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Multiple studies done on rats, dogs, gerbils and other sub human primates laid the foundation for conducting clinical trials in human beings for studying the effects of hypothermia in reducing neuronal injury after the patients had been administered cardiopulmonary resuscitation. Compliance with the trials was also readily given by the relatives and friends of people suffering from such conditions as the prognosis for such cases is usually grave. In a paper entitled ‘Resucitative Hypothermia After Cardiac Arrest’, Sterz Fritz and Holzer Michael in 2003 have described the two major trials undertaken in this specialty in different parts of the world. In the Australian study, 77 patients who had suffered cardiac arrest with known cardiac origin (ventricular fibrillation and tachycardia) and had been revived to the stage of regaining spontaneous circulation were randomly assigned to either hypothermia or normothermia. Hypothermia was induced with the aid of cool ice packs. 49% of the patients subjected to hypothermia had a good outcome while only 26% of the patients subjected to normothermia did so. In another major European study which was multicentric in nature, 275 patients were selected and subjected to hypothermia while using a well planned exclusion and selection criteria. The cooling method used was a novel one using air cooled mattresses. The target hypothermia temperature was attained by the use of additional aids like cooling pads if there was any variation in certain cases. Hypothermia was maintained for 24 hours after which the patients were rewarmed. Te trial resulted in establishing a strong case for the use of this technique as marked improved was seen in the group subjected to hypothermia. Therapeutic mild hypothermia was finally accepted as the first line therapy, with proven efficacy in the post resuscitation period. When the international resuscitation guidelines were revised in 2005, therapeutic mild hypothermia was implemented as a standard therapy. The European Resuscitation Council (ERC) recommendations are as under: • Unconscious adult patients with spontaneous circulation after out-of-hospital ventricular fibrillation (VF) cardiac arrest should be cooled to 32–34°C. Cooling should be started as soon as possible and continued for at least 12–24 hours. • Induced hypothermia might also benefit unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest due to a non-shock able rhythm, or cardiac arrest in hospital. • A child who regains a spontaneous circulation but remains comatose after cardiopulmonary arrest may benefit from being cooled to a core temperature of 32–34°C for 12–24 hours. The use of cooling devices however has not been standardized as yet and different approaches and devices are being used for the purpose (Sterz Fritz, 2003). Different methods used till date are ice bags, blankets containing circulating coolant, cold carotid artery infusions, single carotid artery perfusion with extra corporally cooled blood, a helmet with chemical cooling capabilities, a cooling cap filled with -30°C solution, ice water nasal lavage, cardiopulmonary bypass, cold peritoneal lavage and even drugs. According to Sterz Fritz(2003), cooling using vein to vein extracorporeal blood shunt, pharyngeal cooling, peritoneal and pleural lavage are possible but not generally used. He agrees that extracorporeal blood cooling methods are effective, but too invasive to apply in the pre hospital setting and even in most emergency departments. Surface cooling with cold air provides a non-invasive method. A new method of intravascular cooling with catheters provides a very effective method to reduce the body temperature and keep it at the desired level. Sterz has commented that the use of conventional techniques by infusing cold fluids holds greater promise as it had been substantiated with studies by Rajek A et al, 2000 and Bernard S et al, 2003. Bernard S. A., 2005 has enlisted some other developments in the application of hypothermia after cardiac arrest. Some of these are automated surface cooling/warming devices which allow tight control of body temperature in the ICU. These non-invasive devices improve the control of body temperature, particularly during the rewarming phase. Intravascular cooling devices, according to Bernard are very expensive and require additional training for insertion by medical staff. The Department of Health and Aging in Australia has published a study on the development of a new system ‘Coolgard™ 3000 Catheter Thermal Regulation System: Endovascular hypothermia induction for treatment of comatose survivors of ventricular fibrillation cardiac arrest in September 2005. The description of the equipment although Copyrighted is available for free reproduction as such and is as follows: ‘The CoolGard™ Temperature Control System consists of a temperature monitor, temperature controller and heat exchanger units, and a pump, supplying the temperature controlled sterile saline to the patient via an indwelling catheter (United States Food and Drug Administration 2005c). Data from the temperature monitor is integrated into the system via software that controls the temperature of the sterile saline to be circulated through the catheter to maintain the desired body temperature. The Icy™ catheter is a triple lumen intravascular catheter. The shaft of the catheter has three cooling membranes. Two of the catheter’s lumens are used to circulate cooled sterile saline to exchange heat with the central venous blood supply. The third lumen of the Icy™ catheter is a standard guidewire lumen that can be used as an infusion lumen. The catheter is placed in the inferior vena cava via the femoral vein. Chilled sterile saline is pumped from the CoolGard™ unit through the Icy™ intravascular heat exchange catheter. The catheter has a closed loop system, such that the cooled saline flows from the CoolGard™ unit into the Icy™ catheter, then back to the CoolGard™ System. The cooled saline does not enter into the patient’s circulation; rather, it flows through the indwelling Icy™ catheter, which in turn, exposes the venous circulation to the cooler temperature (Al-Senani et al 2003). The device induces cooling at a rate of 0.05–1.5°C per hour.’ The study concludes that trials have been conducted using this system but there is currently insufficient high level evidence to assess the effectiveness of hypothermia induction with the CoolGard system. The system has also been approved for use by the United States Food and Drug Administration in 2005. Problem Statement As this area of novel therapy for cardiac arrest is relatively new, further studies need to be carried out in order to substantiate the research till date and find any flaws or new insights into the area. Cardiac arrest is invariably a serious medical emergency and the prognosis is usually poor. It is almost impossible to save the life in most cases and whatever is possible within the human medicine research till date is tried in such cases. Appropriate protocols have been developed to handle such cases by using pharmaceutical, surgical and other procedures like cardiopulmonary resuscitation. Induction of hypothermia has shown promise in recent times with increasing evidence of neuronal recovery in controlled clinical trials. Some of the areas which have not been explored till now are as follows: 1. Variations if any due to age, sex and ethnicity. 2. The most appropriate cooling procedures to induce hypothermia. 3. Application of the procedure in cardiac arrest due to reasons other than ventricular fibrillation and arrhythmia. 4. Appropriate time span for cooling and rewarming. 5. How exactly does the induction of hypothermia leads to neuronal recovery and the underlying physiological mechanisms. Whether these mechanisms can be duplicated by other means than hypothermia. 6. Development of portable equipment to induce hypothermia as the time span between cardiac arrest and therapeutic intervention is a critical factor. Issues concerning resuscitative cooling are still unanswered and need further study. The issues identified till date are whether the cooling should be initiated during cardiac arrest immediately or after the initiation of the traditional and time tested life support measures. Is it sufficient to achieve hypothermia rapidly after the restoration of spontaneous circulation? For how long the cooling should be maintained if initiated according to the present set standards? How soon and in what time span should the rewarming be carried out? What is the optimum temperature to be maintained in hypothermia? Successful management of therapeutic mild hypothermia comprises more than mere cooling of the patient (Schneider A. et al, 2006). As human body is programmed to maintain the normal body temperature of 37°C forced reduction of body temperature will result in the activation of endogenous homeostatic mechanisms by the hypothalamus to recover body temperature by means of vasoconstriction and shivering. Appropriate means and methods need to be developed to suppress these physiological reactions. This has to be achieved by using drugs like analgesics, sedatives and narcotics. Induction of hypothermia by purely pharmacological means is also under current investigation. For this purpose a novel idea is being explored which aims to induce therapeutic hypothermia by means of drugs such as serotonin, opioid and dopamine agonists as well as neuropeptide neurotensin. Experiments are being done to explore this approach. The body’s reaction to normalize the body temperature can be suppressed by readjusting the individual’s thermo-regulatory set-point in the hypothalamus to lower temperatures with the aid of such drugs. Aims and Objectives Thus a modern study can be designed keeping above facts in view. The study should aim at identifying the most appropriate cooling apparatus and the duration of applying hypothermia as numerous approaches to inducing hypothermia have been tested successfully. The study can ideally be conducted in hospitals which are located in highly urbanized areas where cardiac arrests are common due to the sedentary life style of people. The ideal group should cover an age range of 40-60 years as this the most common age group where successful therapy holds some promise of recovery. People both above and below these age groups are subject to idiosyncrasies due to unpredictability in the lower age group and complicated medical status in the geriatric group. The already satisfactory studies conducted in both Europe and Australia need to be based as the stepping stones to further research. Adequate provisions should be made to ensure the rapid hospitalization of identified patients who are at risk of suffering a cardiac arrest from their medical history. This should receive prime attention as the rapidity of using the technique is an extremely vital issue of the procedure. Appropriate statistical tools need to be used and the trial made a double blind study which was the missing element in the European trial. Double blind approach can be ensured by adopting the hypothermia procedure as a routine practice much before the commencement of the trial in exclusively selected cardiology departments of multi specialty hospitals. Mobile cardiac care units with intensive care facility within should be available at the centers where the study is proposed to be conducted. As intracranial pressure was not monitored in the earlier study, it can be done in a prospective new study as brain is a very sensitive area subject to dangerous levels of pressure when systemic fluid therapy is concurrently administered along with a multiplicity of centrally acting drugs. Minimum invasive procedures need to be used as trauma can further aggravate the condition. Complications arising due to hypothermia such as infections need to be addressed beforehand and adequate protocols worked up as a preventive measure to tackle such situations. As successful use of hypothermia has already been established in providing better neuronal recovery in previous animal studies and human clinical trials, a null hypothesis can ideally be used to test the two groups, i.e. the patients subjected to hypothermia and the other ones who are kept under normothermic conditions. The null hypothesis, H0, represents a theory that has been put forward, either because it is believed to be true or because it is to be used as a basis for argument, but has not been proved. In a clinical trial of the new method of using hypothermia in patients of cardiac arrest with restores circulation, the null hypothesis might be that the new method is no better, on average, than the use of normothermia. We would write H0: there is no difference between the two methods on average. We give special consideration to the null hypothesis. This is due to the fact that the null hypothesis relates to the statement being tested, whereas the alternative hypothesis relates to the statement to be accepted if / when the null is rejected. The final conclusion once the test has been carried out is always given in terms of the null hypothesis. We either "Reject H0 in favor of H1" or "Do not reject H0"; we never conclude "Reject H1", or even "Accept H1". If we conclude "Do not reject H0", this does not necessarily mean that the null hypothesis is true; it only suggests that there is not sufficient evidence against H0 in favor of H1. Rejecting the null hypothesis then, suggests that the alternative hypothesis may be true. The study will be a quantitative study because to arrive at a statistically significant result, a significantly large sample size should be there i.e. the number of patients chosen should be large enough to arrive at statistically significant conclusion with minimum error and variation. The Utstein style (Cummins et al, 1991) is an accepted method for data collection in this type of study and has been successfully used in the majority of trials in such studies. As the cooling method to induce hypothermia by the newly developed equipment in Australia has been approved for use, it can be considered as the means for inducing hypothermia in this trial leaving little scope for variation in cooling to arrive at better and a more significant statistically true analysis. Grant Proposal It is proposed to conduct a clinical trial on the efficacy of inducing hypothermia as a therapeutic measure in patients suffering from cardiac arrest in the age group of 40 to 60 years in a multi centric study where the new method of inducing hypothermia by CoolGard Temperature Control and Maintenance system will be used to provide uniformity in design and pattern to all the patients. The studies will shortlist cardiac patients with known cardiac problems with ventricular arrhythmia and fibrillation as their primary symptoms based on electrocardiography data. Already established time durations of hypothermia will be used in the patients presented at the clinic subsequently on suffering cardiac arrest and who have received preliminary cardio resuscitative first aid successfully up to the stage of restoration of blood circulation. Means and methods will be employed to make it a double blind study and take care of the subsequent infections in patients who have been subjected to such procedures. The study aims to minimize and analyze the neuronal recovery rates by employing prescribed recovery endpoints as the ultimate aim. References: 1. Al-Senani, F. M., Graffagnino, C. et al (2004). A prospective, multicenter pilot study to evaluate the feasibility and safety of using the CoolGard System and Icy catheter following cardiac arrest, Resuscitation, 62 (2), 143-150. 2. Bernard S.A., (2005). Hypothermia Improves Outcome From Cardiac Arrest, Critical Care and Resuscitation 2005; 7: 325-327 3. Bernard SA. Induced hypothermia in intensive care medicine: A review. Anaesth Intens Care 1996;24:382-388. 4. Bernard SA, Buist MD, Monterio O, Smith K. The induction of hypothermia after cardiac arrest using large volume, ice-cold intravenous fluid. Resuscitation 2003;56:9-13. 5. Bernard SA, Gray T, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557-563. 6. Bigelow WG, Lindsay WK, Greenwood WF. Hypothermia: its possible role in cardiac surgery: an investigation of factors governing survival in dogs at low body temperatures. Ann Surg. 1950;132:849–866 7. Birt David, Thomas BG & Wilson Iain, Resuscitation from Cardiac Arrest, Update in Anaesthesia-Practical Procedures, Issue 10 (1999) Article 6: Page 1 of 4, Royal Hospital for Sick Children, Glasgow 8. Colbourne F, Corbett D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci. 1995;15:7250–7260 9. Coolgard™ 3000 Catheter Thermal Regulation System: Endovascular hypothermia induction for treatment of comatose survivors of ventricular fibrillation cardiac arrest. September 2005 National Horizon Scanning Unit Horizon scanning prioritising summary Volume 10, Number 4: Australian Government, Department of Health and Ageing 10. Cummins RO, Chamberlain DA, Abramson NS, et al. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein Style: a statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Circulation 1991;84:960-75 11. Hitchcock C, Strobel C, Haglin J, Wilson J. Use of prolonged moderate hypothermia in postoperative care. Arch Surg. 1962;85:549–556 12. Holzer M, Universitätsklinik für Notfallmedizin, Vienna, Austria. Feb. 2002, mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. The hypothermia after cardiac arrest study group* 13. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med. 1993;21:1348–1358 14. Leonov Y, Sterz F, Safar P, Radovsky A, Oku K, Tisherman S, Stezoski SW. Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. J Cereb Blood Flow Metab. 1990;10:57–70 15. Merck Manual, Online Edition 16. Rajek A, Greif R, Sessler DI, et al: Core cooling by central venous infusion of ice-cold (4degrees C and 20 degrees C) fluid: isolation of core and peripheral thermal compartments. Anesthesiology: 2000, 93:629-637 17. Reuler JB. Hypothermia: pathophysiology, clinical settings and management. Ann Intern Med. 1978;99:519–527. 18. SKULEC R., KOVARNIK T, DOSTALOVA G., KOLAR J., LINHART A. (2008) Induction of mild hypothermia in cardiac arrest survivors presenting with cardiogenic shock syndrome Acta Anaesthesiologica Scandinavica 52 (2) , 188-194 19. Schneider Andreas, Popp Erik and Böttiger Bernd W, 2006 Therapeutic Hypothermia After Cardiac Arresta A report by Student, Anesthesiologist, and Associate Professor of Anesthesiology, Department of Anesthesiology, University of Heidelberg 20. Sterz F, Safar P, Tisherman S, Radovsky A, Kuboyama K, Oku K. Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. Crit Care Med. 1991;19:379–389 21. Sterz Fritz & Holzer Michael, 2003 SAEM ANNUAL MEETING HANDOUT, RESUCITATIVE HYPOTHERMIA AFTER CARDIAC ARREST.Department of Emergency Medicine, University of Vienna, Austria (Chairman: Univ.Prof.Dr.med. Anton N. Laggner) 22. Zeiner A, Holzer M, Sterz F, et al: Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest. A clinical feasibility trial. Hypothermia After Cardiac Arrest (HACA) Study Group. Stroke: 2000, 31:86-94. Read More