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LAPORAN AKHIR ELECTIVE STUDY III HEMOGLOBIN CONCENTRATION AND CARDIAC FUNCTION PROFILE ON PEOPLE LIVE AT 1500 M ABOVE SEA LEVEL Oleh : Made Bhuwana Putra 1002005181 Pembimbing : dr. I Putu Adiartha Griadhi, M Fis FAKULTAS KEDOKTERAN UNIVERSITAS UDAYANA DENPASAR 2013 TRAVEL

Proposal Penelitian Hemoglobin High Altitude (Repaired)

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TRAVEL MEDICINELAPORAN AKHIR ELECTIVE STUDY IIIHEMOGLOBIN CONCENTRATION AND CARDIAC FUNCTION PROFILE ON PEOPLE LIVE AT 1500 M ABOVE SEA LEVEL

Oleh :Made Bhuwana Putra1002005181

Pembimbing :dr. I Putu Adiartha Griadhi, M Fis

FAKULTAS KEDOKTERANUNIVERSITAS UDAYANADENPASAR2013

CHAPTER IINTRODUCTION

1.1 BackgroundMore than 140 million people worldwide live more than 2500 m above sea level. 80 million of them live in Asia. Even in Bali, there are 90.150 people who live at approximately 1500 m above sea level. 1, 2 Both the high altitude physiologist and the intensivist are challenged by the human organism in a hypoxic environment and the true research potentials presented by high altitude, where the body is subjected to an essentially isolated hypoxic challenge, are only just beginning to be realised. The heart and pulmonary circulation in healthy highlanders have distinct features in comparison with residents at sea level. people native to high altitude (HA) environments live in an environment of hypobaric hypoxia with low ambient partial pressure of oxygen. As a consequence, they develop alveolar hypoxia, hypoxemia, and polycythemia. Despite this, healthy highlanders are able to perform physical activities similar to and often even more strenuous than those of people living at sea level (SL). This phenomenon has been ascribed to adaptive mechanisms that occur at sequential steps of the oxygen transport system with the main purpose of decreasing the total pO2 gradient from ambient hypoxic air to mixed venous blood at the tissue level. 1,2All of these latter consequence may happens because of the difference of the atmospheric pressure at high altitude and sea level. Native highlanders show larger lung capacities than do their lowland counterparts in a manner that transcends genetic background. There are several obstacle in the environtment-mitochondria route of oxygen-called oxygen cascade-which makes the oxygen that we inspired will not be fully administered to mitochondria. And this phenomenon is exagerated in high altitude environtment which has lower atmospheric pressure than at sea level. 3We can be assured that highlanders living at more than 2500 m above sea level have all the physiology changes, now what we were concerned more is whether people who lives at 1500 m have distinct feature concerning their cardiac function and hemoglobin concentration. We can phisycally identified people native to kintamani region in bali (1500 m above sea level) have red colored skin and cheeks which cant be seen in people lives in Denpasar which is at sea level. This fact strenghten our opinion that even people who lives at 1500 m have their own distinct feature related to the amount of their hemoglobin concentration that contribute to their adaptation to the hypoxic environtment of high altitude. 1.2 Problem IdentificationBased on the background above, the author finds several problems as follow: 1.2.1 How does the hemoglobin concentration profile of people who live at 1500 m above the sea level?1.2.2 How does the cardiac function of people who live at 1500 m above the sea level measured with Ecg?1.3 ObjectiveBased on problems above there are several objectives as follows:to know the hemoglobin concentration and cardiac function of people who lives at 1500 m above the sea level.1.4 BenefitSome of benefits in this writting are as follows:This study will be useful to increase the knowledge in this particular area and might be used for further research.

CHAPTER IILITERATUR REVIEW

2.1 Oxygen Cascade transfer of oxygenAerobic organisms maintain O2 homeostasis by responding to changes in O2 supply and demand in both short and long time domains. The effective transfer of O2 from the environment to mitochondria is critical for aerobic organisms. Thus, rapid changes in O2 supply or demand, as might accompany brief exposures to environmental hypoxia or arise from exercise, are typically met with acute cardiorespiratory reflexes that maintain tissue O2 homeostasis.3To know better about the respiratory adaptative response of body towards high altitude environtment we should know how this process of oxygen intake occurs normally. Dry air at sea level where the barometric pressure is 1 atmosphere (101.325kPa) contains 20.95% oxygen. Thus the partial pressure of oxygen is an estimated (0.21 x 100kPa) = 21kPa. When air is inspired it is humidified and thus the partial pressure of oxygen is reduced by the water vapour content (6.3kPa). Thus the inspired partial pressure of oxygen is an estimated (0.21 x (100kPa 6.3kPa)) = 19.8kPa.At the alveolus, the oxygen is mixed with carbon dioxide. The ratio of the amount of carbon dioxide produced to oxygen consumed is determined by the respiratory quotient (RQ), which further reduce the amount of oxygen. Thus the alveolar partial pressure of oxygen is an estimated (19.8 5/0.8) = 13.6kPa.Gas exchange occurs at the alveolar-capillary interface with oxygen (and carbon dioxide) moving across this very thin membrane (typically 0.5 micrometres thick) by diffusion down its partial pressure gradient. The total area available for gas exchange is a huge 50-100m2 as a result of the vast number of alveoli in the normal lung (typically 300 million): the resistance to gas diffusion between the gas and blood phases is consequently very low. Oxygenated blood from the pulmonary circulation is mixed with a small amount of blood in the arterial system that will have bypassed oxygenated alveoli. This is known as venous admixture or physiological shunt and consists of blood from the bronchial circulation, Thebesian vessels (cardiac veins draining directly into the cardiac cavities) and blood that has passed areas of poor ventilation.The reference value for the partial pressure of oxygen in arterial blood (PaO2) is 10.3kPa to 13.3kPa. Beyond childhood, there is a progressive reduction with increasing age. At tissue level oxygen diffuses from capillary blood and ultimately reaches the mitochondria within the cells where cellular respiration occurs. At this point the partial pressure of oxygen is 1 5kPa. The mitochondrion will continue to respire aerobically until the partial pressure of oxygen falls below the Pasteur Point. This is thought to be 0.15-0.3kPa. Inspired air is then warmed and saturated with water vapour in the upper airways

Figure 1 illustrates the cascading partial pressure of oxygen through the respiratory system. The ranges for partial pressures are shown for arterial blood and the mitochondrion. Artery on Everest shows the average value for the partial pressure of oxygen in the arterial blood of 4 climbers at 8,400m on their descent from the summit of Mt. Everest. An oxygen partial pressure of < 8kPa is accepted as the threshold for respiratory failure.4

Figure 1. Oxygen cascade on normal person2.2.2 Peripheral tissue changes

Despite the importance of this final step in the delivery ofoxygen to the mitochondria, relatively little is knownabout the adaptive changes which take place in the peripheral tissues at altitude. Capillary density in muscle is unchanged, although the average diameter of muscle fibres appears to be reduced.2 Possible advantage of this change would be to reduce the distance that oxygenhas to diffuse from the capillaries to the mitochondria. Muscle myoglobin appears to be increased at altitude improving oxygen diffusion through muscle cells.2 This, perhaps, acting as an oxygen reservoir during periods of profound cellular hypoxia.

2.2 Effect of high altitude exposure to normal cardiovascular systemThe role of the cardiovascular system is simple; to drive the delivery of oxygen to the tissues need it and carry away the metabolic effluent. It needs to respond to the changing metabolic needs of the tissues in such a way that oxygen delivery meets demand. How it does this is complex, even more so at altitude, where the reduced barometric pressure-compared with one at the sea level- and therefore partial pressure of oxygen, cause further stress on the body.42.2.1 CirculationThe major effects of acute hypoxia on the heart and lung are shown in Figure 3. Hypoxia directly affects the vascular tone of the pulmonary and systemic resistance vessels and increases ventilation and sympathetic activity via stimulation of the peripheral chemoreceptors. Interactions occur between the direct effects of hypoxia on blood vessels and the chemoreceptor-mediated responses in the systemic and pulmonary circulation.4

Figure 2. Effect of hypoxia towards the cardio-pulmonary system

The heart and pulmonary circulation in healthy people living at HA exhibit important physiological and anatomic characteristics, which resemble those that occur in chronic clinical conditions associated with alveolar hypoxia, hypoxemia, and polycythemia. Healthy HA natives have pulmonary hypertension (PH), right ventricular hypertrophy (RVH) and increased amount of smooth muscle cells (SMCs) in the distal pulmonary arterial branches. All these findings become exaggerated when healthy highlanders lose their capacity for adaptation and develop chronic mountain sickness (CMS).2Several mechanisms appear to regulate local oxygen delivery according to the needs of the tissues; for instance, the release of ATP from red blood cells and the generation of NO by various ways appear to regulate local oxygen delivery according to the needs of the tissue. These mechanisms may decrease with prolonged stay at high altitude when oxygen content of the blood increases because of ventilatory acclimatization, an increase in hematocrit associated with plasma volume reduction, and an increase in red blood cell mass due to erythropoiesis.5

2.2.2 Heart

The consequences of acute hypoxia are an increase in heart rate (both at rest and on exercise), myocardial contractility, and cardiac output for the first few days. The higher the altitude, then the greater the increase in heart rate. With acclimatization, cardiac output falls at rest and on exercise in association with a decrease in left ventricular work but an increase in right ventricular work. On exercise however, even in acclimatised subjects, heart rate for a given work load is greater than at sea level except at maximal exercise where maximal heart rate is reduced compared to sea level values.4 This may be due to decreasing maximal oxygen (VO2max) consumption we can get at high altitude environtment.

2.2.2.1 Myocardial Contractility and Coronary Circulation

The findings suggest that in spite of the severe hypoxaemia, pulmonary hypertension and reduction in preload, cardiac contractility is maintained even at a simulated altitude of 8000m.2Permanent residents at high altitude have a reduced coronary blood flow compared to sea level residents because of the increased oxygen of arterial content after by a process of acclimatization. And yet there appears to be no increase in incidence of myocardial ischaemia. One explanation is that there is a greater density of coronary artery terminal branches in these residents compared to sea level control.42.2.2.2 Stroke Volume

Both cardiac output and heart rate rise acutely with exposure to hypoxia and there is no consistent change to stroke volume. Once acclimatized a subjects cardiac output during exercise returns towards sea level values whereas heart rate continues to be elevated. Thus stroke volume must be reduced and this has been confirmed in several studies.1 This is not due to a loss of myocardial contractility but perhaps due to a reduction in plasma volume and therefore preload or a reduction in cardiac filling time secondary to the increased heart rate.2.2.2.3 Blood Pressure

Blood pressure changes little with acute exposure to altitude; however there is usually an increase for the first few weeks when lowlanders travel to altitude. This is probably due to an increase in the sympathetic drive and vascular tone.4

2.3 Physiology development of HA natives Healthy HA natives have pulmonary hypertension (PH), right ventricular hypertrophy (RVH) and increased amount of smooth muscle cells (SMCs) in the distal pulmonary arterial branches. PH with a mean value of PAP (PPA) of _60 mm Hg was found in HA newborns, a finding similar to that described at SL. After birth, however, the changes in PAP were very different. In contrast to the fast decline at SL, PPA at HA decreased slowly, and a mild or moderate degree of PH remained until adult age. The calculated pulmonary vascular resistance (PVR) was 5 times greater at HA than at SL. The postnatal persistence of PH at HA implies a delayed closure of ductus arteriosus and, as a consequence, an increased prevalence of patent ductus arteriosus at HA. The evidence indicates that the main factor responsible for PH in healthy highlanders is the increased amount of SMCs in the distal pulmonary arteries and arterioles, which increases the PVR. Vasoconstriction is a secondary factor because the administration of oxygen decreases the PAP only by 15% to 20%. Hypervolemia, polycythemia, and increased blood viscosity, although considered causal factors in earlier studies,17 are now considered secondary factors. The main role of the structural changes in the pulmonary vasculature is confirmed by the slow decline of PAP, which becomes normal after 2 years of residence at SL.1,2 These development process of adaptation is what makes them differs from those who live at sea level.

2.3.1 Ecg profile on HA nativesThe effect of chronic hypoxia due to high altitude on the right side of the heart is of particular interest. Complementary fluoroscopic and ambulatory continuous electrocardiogram studies have demonstrated that an increase in the volume of right cavities rather than a total involvement is responsible for heart enlargement. Measured QT interval at high altitude was prolonged in comparison with that at sea level as long as the R-R interval was the same. It was also noted that the corrected QT interval at high altitude both in daytime and nighttime was significantly prolonged when compared with that obtained at sea level, and in particular, the corrected QT interval at night was prolonged markedly at high altitude.5 The mechanism for the production of right ventricular hypertrophy at high altitudes appears to be the increased pulmonary pressure that has been found at this altitude.

2.4 Haemodynamics

2.4.1 Plasma Volume

At altitude there is generally a reduction in plasma volume as a result of diuresis. This is likely to be caused by changes in the feedback loops as a result of hypoxia. Hypoxic stimulation of the carotid bodies reduces sodium reabsorption in the kidneys via neural pathways leading to both a natriuresis and diuresis. ANP (and BNP) is produced in the right atrium and is normally released as a result of atrial stretch but more recently has also been shown to be released in the presence of hypoxia. The rapid reduction in plasma volume on exposure to high altitude results in an increase in haemoglobin concentration. At the same time as the reduction in plasma volume, hypoxia stimulates renal and hepatic erythropoietin production stimulating erythropoiesis. 4 Thus, this change in plasma volume also has correlation with the regulation of the erithropoiesis process occuring on high altitude environtment.

2.4.2 Regulation of Hemoglobin Concentration

The EPO gene is induced by hypoxia inducible factor-1 (HIF-1). Interestingly this nuclear factor, which is rapidly broken down in normoxia, but accumulates in hypoxia, is responsible for inducing multiple other genes that may well play a part in acclimatisation and adaptation to altitude; products include lactate dehydrogenase, nitric oxide synthase and vascular endothelial growth factor.There is an elevation in EPO production within the first 2 hours of hypoxia, peaking at 24-48 hours and declining to normal The EPO gene is induced by hypoxia inducible factor-1 (HIF-1). Interestingly this nuclear factor, which is rapidly broken down in normoxia, but accumulates in hypoxia, is responsible for inducing multiple other genes that may well play a part in acclimatisation and adaptation to altitude; products include lactate dehydrogenase, nitric oxide synthase and vascular endothelial growth factor.There is an elevation in EPO production within the first 2 hours of hypoxia, peaking at 24-48 hours and declining to normal. However, the benefit of an increase in haemoglobin on the oxygen content of the blood is offset by the fact that it increases viscosity; there is an exponential increase when levels rise above 18g/dl. Blood flow is inversely proportional to viscosity and at high levels the increase in resistance of flow through the pulmonary and systemic circulation is sufficient to reduce cardiac output. Hence although oxygen content may be increased, oxygen delivery to the tissues may be reduced. 1,4

Until this day most of the research are concerning adaptation of people live at more than 2500 m above sea level. But we know that theoritically adaptation starts at 1500 m above sea level. The result of this study can furthermore be continued in other region with more samples as indicated in statistic calculation. If the result is constant then we can conclude that there are actually some kind of adaptation even in people live at 1500 m above the sea.

CHAPTER IIISTRUCTURAL CONCEPT 3.1 ConceptFrom the theory and problem identification we can conclude a structural concept as follow:

Phsyiological Acclimatization:Cardiac systemHemoglobin

People live at 1500m

Figure 3. Research sturctural concept

Condition in which the natives of high altitude live which is hypoxic makes their physiology adapt to it by increasing several aspect including ventilation, cardiac output and hemoglobin concentration, this what differentiate them with people live at sea level altitude. We suspect that people live at moderate altitude (1500 m) have adapt compare to those who live at sea level altitude.

CHAPTER IVRESEARCH METHOD

4.1 Place and Time of ResearchResearch will be conducted on January 2014 at certain Banjar in Kintamani

4.2 Research DesignThis research is categorised as descriptive study, using cross sectional design. Cross sectional design is design that involve observation of all of a population or, in this study, representative subset at one spesific point of time. The diagram of this study can be seen in figure 4 below:

PopulationPeople live at 1500 mS1HemoglobinCardiac Function

Figure 4. Diagram of descriptive cross sectional research design

4.3 Population and Sample

4.3.1 PopulationPopulation of this research is all adult live in Kintamani which is 1500 m above sea level, where target population in this research is all healthy adult individual who live at certain banjar in Kintamani.

4.3.2 Amount of Sample and Sample Taking Method

4.3.2.1 Amount of sampleThe total amount of sample will be calculated using binomunal proportions formula which suits the cross sectional study in condition that we dont know the number of population and no previous research been done before: n = Z2 p (1-p)dn = amount of minimum sample requiredZ = degree of confidencep = powerq = 1-pd = error limit

50 = 1,962 0,8 0,3 0,01n = 50

4.3.3 Sample Inclusion CriteriaThere are several criteria made to distinguish samples we are going to use in this study as follow:4.3.3.1 high altitude resident is healthy adult individual in productive age (15 64) who live at Kintamani and come to a certain banjar in that area, willing to be taken as sample and have no any heart and anemia disease. 4.3.4 Choosing SampleSamples will be choosed by using quota sampling method based on the list of resident in certain banjar in Karangasem which either have inclusion or exclusion criteria. 27 samples is needed in this study, by using random numeric table we can get 27 samples start from first selection on random number and next two number as the next sample. We are doing this over again unil we got 27 samples.

4.4 Research VariableResearch variable that we are going to use in this study is high altitude resident, hemoglobin concentration, and cardiac function which will be descrive in tthe next section.

4.5 Variable Operational Definition

4.5.1 high altitude resident is healthy adult individual who live at Kintamani, come to certain banjar, willing to be taken as sample and have no any heart and anemia disease.

4.5.3 Hemoglobin concentration is the amount of hemoglobin in blood taken from the samples which fit in inclusion criteria using venipuncture method with spite and EDTA tubes, and the amount of blood taken for each sample must fully filled the 4mL EDTA tubes or minimally 1,5 mL for accurate interpretation.

4.5.4 Cardiac function is heart rate measurement and detection of right ventricle hyperthropy measured by the Ecg Fukuda made from Japan by placing electrodes on the subject.

4.6 Data Collection Method4.6.1 ToolsSpesific tools that we are going to use in this study are:1. Fukuda Ecg from Japan used to measure the cardiac function of each samples by putting electrode on samples.2. Spite and sampling bottle (4mL EDTA tubes) for taking blood samples which is then delivered to Denpasar for further analysis.

4.6.2 MethodWe will gather all of the samples which were chosen randomly before from the list of resident at certain banjar in Kintamani. Then we collect the data from samples using spite and EDTA tubes for their hemoglobin which is then analysed at the laboratorium in Sanglah, Denpasar. And their cardiac function using ecg. 4.7 Data AnalysisAfter we succesfully gathered all data that we need, we will do systematic and logical arrangement to the data. The analysis method that we are going to use is argumentative descriptive analytic method.

REFERENCES

1. Penaloza, Dante, Javier Arias-Stella. The Heart and Pulmonary Circulation at High Altitudes : Healthy Highlanders and Chronic Mountain Sickness. 2007. Circulation. 115:1132-11462. N. P. Mason. The physiology of high altitude: an introduction to the cardio-respiratory changes occurring on ascent to altitude. 2000. Current Anaesthesia and Critical Care 11, 34413. Brtsch, Peter, J. Simon R. Gibbs. Effect of Altitude on the Heart and the Lungs. 2007. Circulation. 116:2191-22024. Hooper, T, A Mellor. Cardiovascular Physiology at High Altitude. 2010. J R Army Med Corps 157(1): 23-285. Rotta, Antdres, Andres Lopez. Electrocardiographic Patterns in Man at High Altitudes.1959.circulation. 19:719-728