Science of High Altitude Pulmonary Edema.

 

                                             Science of High Altitude Pulmonary Edema

                                                      PKGhatak, MD

Airlines are carrying a large number of people to high altitude sky resorts and mountain climbing facilities. These popular recreational activities also put people at risk of mountain sickness and acute pulmonary edema.

At sea level, the partial pressure of oxygen (Pio2) in the air is 160 mm Hg. At 8,000 ft the Pio2 is 120 mmHg, at 11,000 ft. above sea level the Pio2 is 87 mmHg, and at extreme high altitude, 18000 ft., the Pio2 is only 50 mm Hg.

At any altitude above 4,000 ft. the blood level of oxygen is low and becomes lower at higher and higher altitudes.

Air enters the alveoli of the lungs with inhalation. On the way to the alveoli, the air becomes fully saturated with water vapor. At a body temperature of 98.8 degrees F, the partial pressure of H2O is 47 mmHg, PiO2 is diluted as air enters the alveoli and Pi02 becomes (160-47) 113 mmHg. The blood in the capillary is separated from the alveolar air by only one layer of cells. The oxygen(O2) of air first gets dissolved in the alveolar fluid and then rapidly binds with the hemoglobin of blood because of the high affinity of oxygen to hemoglobin and forms a loose compound oxyhemoglobin. The mixed venous blood Pvo2 is 40mmHg, favoring oxygen flow toward the blood due to a pressure gradient of 83 mmHg (113- 40).

When this is happening, carbon dioxide (CO2) of blood is moving in the opposite direction – from blood into the alveoli, again due to the pressure gradient of 40 mmHg of blood to the + 0 mmHg of alveolar air. The CO2 binding is accelerated by the presence of enzymes, carbonic acid anhydrase. As little as 2 to 10 mmHg pressure gradient CO2 can move rapidly and completely.

As the blood leaves the alveoli and returns to the left side of the heart, the O2 carrying capacity of blood is at maximum – the PaO2(partial pressure of arterial blood) is over 90 mmHg and the O2 saturation (O2 sat) is 98 to 100 %.

Let's look at what happens at 8,000 ft. The Pio2 in the alveoli is 73 mmHg (120 – 47). The O2 gradient is (73-40) 43 mmHg. At 43 mmHg, the O2 sat is 75 %. This is significant. Hypoxemia and patients immediately develop symptoms.

Effects of Hypoxia on Local Population.

The people living in the high plateau of Tibet for over 35000 years. The average altitude of the Tibetan plateau is 11,000 ft. They have developed an advanced adaptive mechanism, and it stands in contrast to the rest of high altitude residents of Ethiopia and Andes Mountain people. In Peru and Bolivia, the present population moved in about 1,100 to 800 years ago and has yet to adopt the full high altitude mechanisms of the Tibetan population.

In Peruvians and Bolivians, the hemoglobin level is higher due to the increased Erythropoietin activity, the minute ventilation is decreased, pulmonary arterial pressure is higher, right ventricular hypertrophy is present, Nitric Oxide(NO) levels are lower compared with Tibetans. They have more complications during pregnancy and childbirth, and newborns have lower weight at birth.

In Tibetan, the mutation of EGLN1 and EPAS1 genes carries the adaptive oxygen sensing and high altitude hypoxic adaptive mechanisms. The hypoxic stimuli of carotid and aortic bodies are muted. There is no hyperventilation. At 85 mmHg, the O2 saturation of the air is over 87%, the nitrogen oxide levels in the lungs and blood are high. The hemoglobin levels are not elevated. The resting ventilation is high, and lung volumes are larger. The smooth muscles of the pulmonary artery are not hypertrophic, pulmonary hypertension does not happen. The weight of newborns is normal.

Effect of Hypoxia on Recent Arrivals.

Acute Mountain Sickness.

On the very day of arrival, symptoms of cerebral anoxia develop. The main symptoms are headaches, dizziness, nausea, anorexia, fatigue and shortness of breath on minimal activities, difficulty sleeping and a mild dry cough. Swelling of the face, hands, and feet develops.

High Altitude Pulmonary Edema (HAPE).

From day 2 to day 4 of arrival, the symptoms are more severe. The shortness of breath at rest develops. The temperature rises to 101F degrees. Palpitation and rapid breathing, mental confusion, incoordination and prostration soon appear. The cough becomes productive of pink frothy sputum and occasionally becomes bloody, labored breathing with gurgling sounds on breathing is heard, cyanosis, a slow heart rate and BP began to fall. Acute respiratory distress and Acute Pulmonary edema set in.

High Altitude Cerebral Edema (HACE).

Anoxia of the brain cells is responsible for increased fluid accumulation in between brain cells and produces persistent headache, dizziness, nausea, the sensation of pins and needles, lethargy, incoordination, loss of sleep, tinnitus, violent behavior and loss of consciousness and seizures.

Pathophysiology of HAPE.

1. Hypoxia producing capillary leaks.

The tight junctions between the type I alveolar cells prevent excess fluid accumulation in the alveolar space. A thin layer of fluid is essential for the normal function of ventilation and gas exchanges. The integrity of the alveolar membrane depends on oxygen; in the hypoxic condition, the alveolar type I cells develop gaps between cell junctions and fluid escapes in the alveolar space. Nitric oxide production is reduced, lack of nitric oxide in the lung results in smooth muscle contraction of the pulmonary arteries and the Pulmonary arterial BP (PBP) is elevated. That produces Right heart strain and hypertrophy. Dr. J.B. Web described the genesis of the capillary leak “The hydrostatic stress that exceeds the load bearing limits of the collagen network [of alveoli] results in rupture of the basement membrane.”

2. Derailed removal of fluid.

Two separate but interrelated paths are present in the lung to ensure fluid removal, these are

A. Starling force driven sodium channels.

B. Na and K iron ATPase dependent trans-epithelial sodium channels.

The functioning of both these channels is defective in hypoxic conditions.

If the foramen ovale was not completely closed the opening of the foramen ovale enlarges and the Right to Left shunt takes place which makes hypoxia more profound and early right heart failure develops. Endothelin-1 activities are reduced and contribute to Pulmonary BP elevation.

 C. Increase in pro-inflammatory markers in the lung.

Analysis of bronchial fluid obtained during the Intubation of HAPE patients shows an increase in pro-inflammatory markers, namely interleukin IL-1 beta, IL-6, IL-8, TNF alpha. In addition, the total cell counts are elevated, and increased lung macrophages are present. Blood levels of LDH, CRP, and total proteins are increased. The monocytes attractive protein1alpha (MIPA1alpha) and monocytes chemo-attractant protein1 and IL8 are significantly higher in Chronic Mountain sickness.

D. The anti-inflammatory markers, IL alpha, IL-10, show no change or levels are decreased.

Chronic Mountain Sickness.

Prolonged stay at high altitude results in the continuation of acute symptoms, in addition, the patients develop sleep disorders. Mental confusion, abnormal behavior, cognitive impairment and various neurological symptoms.

Returnee of a Native of High Altitude.

High altitude people living on a lower plane for an extended period and then on returning to high altitude experience a more severe form of acute Pulmonary edema. The basic reason for this disease is not known.

Diagnosis of HAPE.

Respiratory symptoms in recent arrivals at high altitudes should always alert the possibility of acute mountain sickness or HAPE. This is the primary diagnosis and other possibilities like cardiac failure, PE, and pneumonia should come later.

Shortness of breath at minimal effort, or at rest, temperate elevation, frothy pink sputum, air hunger, cyanosis, tachycardia, and increased rate of respiration are universally present. Moist sounds, rales, on auscultation on both sides, chest x-rays- bilateral mid-zone, bat wing shaped infiltrates, and a low O2 saturation by pulse oximetry should be diagnostic of HAPE.

 

Immediate oxygen is administered by any available source to keep the O2 sat over 90%. Portable Hyperbaric oxygen chambers are generally available or should be made available as soon as possible. An arrangement must be made to take the patients to a lower altitude to a better medical facility.

Medications.

Nifedipine 20 mg tablets are given at 4 hourly to lower Pulmonary hypertension (PAP). Acetazolamide, a diuretic, also lowers PAP by blocking calcium channels, Tadalafil, a phosphodiesterase inhibitor, is also used. A bronchodilator Salmeterol is used to ease breathing.

Dexamethasone is used when cerebral edema is suspected in HAPE with predominant cerebral symptoms.

Prevention of acute mountain sickness and HEPA.

People should consult mountaineering schools/ training centers at the time of preparation for such events. The day before arrival, Nifedipine 80 mg long acting tablets one tablet and on arrival day and onwards one tablet should be taken. No physical activities on the 1^st day. Sleeping at a lower altitude should be considered. Daily hiking/climbing should be limited to 1500 feet.

Use portable oxygen when the pulse oximeter shows saturation below 90 %. And seek advice from the team leader or the guide.

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Non Alcoholic Fatty Liver Disease

 

                                          Non-Alcoholic Fatty Liver

                                        PKGhatak, MD

An ultrasound scan of the abdomen is an unusually simple procedure for investigating abdominal and pelvic conditions. Many patients were found to have fatty liver unexpectedly and unrelated to their symptoms for which ultrasound scans were performed.

Incidence is quite high and is rising not only in the USA but also worldwide. In the USA, about 25 % of people have a fatty liver on ultrasound scan, in India, it is about 35 %.

Chronic alcoholism is a common cause of fatty liver. But it is also detected in high numbers in non-alcoholics. This is now designated as Non-Alcoholic Fatty Liver Disease (NAFLD).

The cause of NAFLD is unknown. People with NAFLD have a high association with Diabetes II, hepatitis C and HIV infections. More causal associations are seen in hepatitis B and A, obesity, physical inactivity, metabolic syndrome - the combination of high BP, obesity around the waist, high triglyceride & LDL cholesterol. Psoriasis, Hypothyroidism, hypopituitarism, Hemochromatosis, sleep apnea, polycystic disease of the ovary, and high fructose soft drinks and prepacked food and frozen TV dinners.

The adverse effect of the medication is known to produce NAFLD -   Acetaminophen. A heavy dose of tetracycline, oral hormone therapy, amiodarone, valproic acid, certain cancer drugs, some HIV drugs.

NAFLD is the initial stage of fatty liver, a more advanced stage of inflammation of the liver leads to a state called Non-Alcoholic Steatohepatitis (NASH). The incidence of NASH in the USA is about 6% of the population and in India, it is about 12 %.

Symptoms.

The majority of patients are symptoms free. Some complaints of vague upper abdominal discomfort, right upper abdominal pain, bloating, and anorexia. Some other patients with more advanced diseases have a loss of weight, enlargement of the liver, anemia, frequent infections, and gastrointestinal bleeding.

Investigation and diagnosis.

Liver enzymes - ALT and AST are elevated, due to liver damage. Platelet count falls due to decreased production of Thrombopoietin, a hormone produced in the liver and needed for platelet generation in the bone marrow.

Later, vitamin K-dependent clotting factor deficiency leads to the prolongation of Prothrombin time. Serum albumin level falls.

MRI of the liver clearly delineates pathological changes in liver cells. A new generation of Ultrasound scans – Fibroscan of the liver is also very sensitive like MRI and detects the degree of fibrosis. Fibrosis is the result of deaths of hepatocytes and inflammatory cell infiltration of the liver. Hepatic cirrhosis is the end stage.

Fibrosis Calculation.

Several institutions have developed a Fibrosis score, corroborated by liver biopsy, based on Age, ASL and ALT, and Platelet count. It is very useful for patients and the treating physician for monitoring progress. This practice has decreased the need for liver biopsy.

Formula : 

 Age ([yr] x AST [U/L])   /   ((PLT [10(9)/L]) x (ALT [U/L])(1/2)). 

Using this formula, patients with a score > 3.25 are likely to have advanced fibrosis whereas those with a score < 1.45 are unlikely to have advanced fibrosis.

A biopsy of the liver is the final confirmatory test, but biopsy is not necessary in the majority of cases.

Complications.

As the NAFLD progresses, the inflammation leads to the development of Steatohepatitis, the next step and ultimately to hepatic cirrhosis. Complications of cirrhosis are bleeding esophageal varices, hypoalbuminemia, ascites, hypersplenism, thrombocytopenia, and hepatic failure.

About 5 % of NAFLD patients with hepatic cirrhosis develop Hepatocellular carcinoma.

Treatment.

No effective drug treatment is available.

A weight reduction of 5 to 7 % of body weight is associated with improvement.

Daily physical exercise or 45 45-minute walk is advocated.

Elimination of Fructose from food and drinks should be done.

Vitamin E as high as 700 IU was advised, but worsening Diabetes and increased prostate cancer risk should be taken into consideration before undertaking such therapy.

Liraglutide with vitamin E is also tried.

Aramchol a combined fatty acid and bile acid conjugate is approved in Israel and in India for use in NASH.

Several anti-fibrosis agents are undergoing trial in the final stages.

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Embolus

                                                               EMBOLUS

                                                   PKGhatak, MD

The word embolus is derived from Greek: en + ballein = in + to throw. In short, it means a wedge or plug. Obstruction of blood vessels by a wedge or plug may result from any of these - a piece of a detached blood clot, a fat globule, air bubble, a broken piece of the indwelling venous catheter, amniotic fluid and IV drug addicts injected contaminated drugs, and in rare instances broken piece of bones and metal fragments during orthopedic surgery.

What happens with the venous embolus/ emboli.

Venous blood returns to the right side of the heart, then goes to the lungs. All formed substances having a size larger than an RBC (red blood cell) are caught in the pulmonary capillaries. The living tissues beyond the site of obstruction suffer severe oxygen lack, undergo various degrees of structural damage or die (infarction).

In patients, with an open foramen ovale or right atrial septal defect, the emboli enter the left atrium, pushed to the left ventricle, from there into the general circulation. Clots can block arteries of the brain, kidneys, GI tract, etc. and result in substantial damage to the organs.

Fat embolism.

Bone marrow contains a large amount of fat and may release fat globules in the blood. Fractured bone or orthopedic surgery, fat molecules are released in the circulation. The fat globules, like venous blood clots, get tangled up in the lung capillaries or go via an open foramen ovale and enter the arterial side bypassing the lungs. In addition, the fat molecules can flatten out and may enter the arterial side of the circulation by one of these mechanisms. 1. The cells of the alveoli are disrupted and allow fat to enter pulmonary veins. 2. Fat molecules thinned out and assume elongated narrow shapes and go past the capillary bed to the venous side and then to the left heart and travel everywhere with the arterial blood,

Air embolism.

In an underwater dive, in a submarine or scuba diving, the nitrogen of air dissolves in a large volume in the blood due to higher pressure – the deeper the depth, the higher the pressure. In a rapid ascent, the nitrogen emerges from blood as gas and forms bubbles in the arteries and veins. Air bubbles obstruct blood circulation and deprive organs of oxygen. In the lungs, the rapid release of dissolved nitrogen can produce enough pressure to rupture the lungs and the lungs may collapse.

In high altitude flying, if the cabin pressure is lost suddenly, then air bubbles form in the blood vessels.

The intravenous line attached to the Porto Cath in the central vein may get disconnected and air can enter. In some instances, the air from the IV tubing is not purged completely; a small amount of air can enter, in most such cases the air will diffuse out via the alveoli and expired breaths but in other instances may produce serious consequences.

Chance of air embolism is a concern in every case involving direct access to central veins - like coronary bypass operation, heart-lung machine, extracorporeal membrane oxygenation, etc.

In childbirth, the freshly separated placental site may allow air to enter the veins of the mother.

Amniotic Fluid Embolism.

In late pregnancy, the placental membrane along the veins can tear open, allowing amniotic fluid to enter the mother's circulation. Amniotic fluid carries cellular debris, hair, urine and meconium of the fetus. In spontaneous miscarriage/abortion/ Caesarean section, amniotic fluid embolism may happen.

Foreign Body Embolism.

IV drug users inject crushed tablets, some of the ingredients of tablets are kaolin, a kind of earth, gum and inert substances. All these are pushed into the vein.

Many of these chemicals produce inflammation and granuloma in the lungs. Repeated exposures produce pulmonary fibrosis. Broken needles, at times, find their way into the lungs causing hemorrhage, pneumothorax and hemothorax.

Venous Thrombus and Pulmonary Embolism.

Blood contains several clotting factors and also clot preventing factors. Blood circulates constantly, that movement prevents blood from clotting. Just like concrete carrying trucks constantly rotate the cement drum to prevent the concrete from solidifying.

Tissue clot promoting factors.

Deep vein thrombosis is seen frequently in these conditions - post surgical patients, multiple fractures, pregnancy and childbirth, cancer chemotherapy. These conditions produce tissue damage and release the Tissue clotting factor.

Stasis of blood in veins.

A prolonged period of sitting, as happens on a long flight on airlines, and in certain jobs, like watching monitor screens constantly, promotes venous clots in the leg and pelvic veins. When blood is stagnant, the tissues use up oxygen and produce anorexic injury to the endothelium of veins and release clot-promoting factors. In congestive heart failure, return of venous blood from below the diaphragm is delayed due to higher pressure in the right atrium. Immobilized fracture of the leg is another risk factor, so also varicose veins.

Antithrombotic protein Thrombomodulin and Endothelial Protein Receptors are downregulated in infections, injuries and hypoxia. The same mechanism also up-regulates the Leukocyte adhesion molecule - P-selectin.

Blood viscosity.

In blood diseases, like polycythemia vera and leukemia, the blood cell volume is elevated. In multiple myeloma, the globulin levels are high. These conditions result in high viscosity which slows circulation and promotes blood clots.

Congenital absence/ deficiency of anticoagulants.

Protein C in association with V Leiden is a potent anticoagulant. About 5% of the Caucasian population of North America has a congenital deficiency of V Leiden. Several other anticoagulation factors like Protein S, protein C, antithrombin, and prothrombin are also inherited. Congenital deficiency of vitamin K dependent factors occurs due to mutation of the VKORC-1 gene.

Acquired clotting factor abnormalities.

Anti-phospholipid syndrome, Nephrotic syndrome, Lupus antibodies to antiphospholipid and in homocysteinemia, Paroxysmal Nocturnal hemoglobinuria promote blood clots. Carcinoma produces various coagulation factor abnormalities. Central venous indwelling catheters - the tip of the catheter often form clots and a clot can propagate. Estrogen therapy - increases liver production of several clotting factors.

Infected Blood clots.

In infections of the heart valves and endothelium (inner layer of the heart) the bacteria produce colonies known as vegetation. These vegetations are fragile and break loose. Arterial blood carries these infected vegetations to the brain, kidney, liver, spleen and other organs.

Detached arterial plaques.

In coronary angiogram/angioplasty procedures, the catheter tips may knock off arterial plaques. These plaques are made up of calcium-cholesterol-cellular derbies and these travel downstream to the pelvis, legs, kidney, etc. Carotid artery plaques may go directly to the brain and cause strokes. Similarly, during surgical repairs of Atrial aneurysms emboli can easily happen.

Consequences of Pulmonary Embolism.

Pulmonary embolism (PE) from breaks away clots from the deep veins is the most common cause of pulmonary embolism. About 400,000 cases are recorded each year in the USA and 40,000 patients die from PE.

The symptoms, diagnosis and treatment.

It is easier to discuss this aspect as 1. Massive pulmonary emboli, 2. Recurrent small multiple pulmonary emboli and, 3. Mixed type.

1. Massive pulmonary emboli.

 It is a life ending event if immediate treatment is not available. Sudden acute onset of shortness of breath, chest pain followed by loss of consciousness and ventricular arrhythmia results from lack of oxygen to vital organs. A chest x-ray may show a lack of the usual darkness of blood in the lung and is called an oligemic lung. EKG shows sinus tachycardia in excess of 120/ min, right axis, RBBB, right ventricular strain and ventricular premature beats or tachycardia. Marked hypoxemia, cyanosis, shock, feeble /absent pulse at the wrist, altered consciousness, and poor renal output are usual findings. Angio CT/ angiogram shows clots in the pulmonary trunk/ main branch and sudden tapering of the caliber of the pulmonary artery.

Treatment is very urgent. A pulmonary artery catheter is inserted and advanced to the site of obstruction. Thrombolytic agents are infused. Otherwise, open chest operation and removal of clots have to be undertaken. A six-month direct oral anticoagulant or vitamin K-dependent \ clotting factors (factor VII, IX, X, protein C, protein S, and Prothrombin inhibition) coumadin are recommended. Underlying clotting factor modification where possible should be done.

2. Chronic small repeated Pulmonary emboli.

The initial episodes of pulmonary emboli may be misdiagnosed as mild asthma attacks, undetermined chest pain, and anxiety attacks. Shortness of breath with mild physical activities develops. Evidence of Pulmonary hypertension develops. Long term anticoagulation is essential to prevent future emboli. In recurrent PE an Inferior vena cava filter is inserted that block the upward movements of clots.

3. Mixed types are the combination of these classes. Thrombolytic therapy and long term direct acting anti-coagulation is appropriate therapy.

Fat embolism.

Fat embolism is underreported. The risk factors of fat embolism are - all major multiple bone fractures, crush injuries, bone marrow transplantation, orthopedic surgery of major joints, IV hyperalimentations, liposuction, acute and chronic pancreatitis, prolonged CPR, splitting sternum in open heart surgery, major burn victims, prolonged use of corticosteroid, fatty liver, sickle cell anemia, thalassemia, etc. When a small amount of fat globules enters the circulation, it may not produce any adverse effect on the body. When intermediary pins were used in hip fractures, fat embolism was common.

More than occasionally, the fat embolism is misdiagnosed as something else and only by autopsy examination is the fat embolism established. 15 % of all autopsies show fat embolism. Fat is a neurotoxin. Cerebral fat embolism produces significant CNS symptoms. Skin petechiae are very characteristic of fat emboli of the skin. A fluoroscopic eye examination is one direct evidence of any embolism.

 A chest x-ray may show only nonspecific vascular congestion. MRI of the brain is most helpful for cerebral fat emboli. Centrum putamen and subarachnoid show edema due to the toxic effect of fat.

Treatment of fat embolism has gone through many therapeutic trials, but none are specific. General vascular support and adequate oxygenation of vital organs decide the treatment outcomes. Mortality is about 10%.

Air Embolism.

Air embolism produces two distinct groups of medical problems.

One that produces pain in joints is known as caisson disease or bends. The other is major symptoms due to blockage of blood flow to vital organs. Occasionally air can block blood entry to the heart chambers. These incidences are not common but time is short for the reversal of the block. Less severe but significant symptoms are due to cerebral anoxia.

Treatment consists of giving oxygen immediately and then oxygen delivered in Hyperbaric chambers. This aspect is discussed in an earlier blog.

Amniotic Fluid Embolism.

Amniotic fluid embolism is a near fatal complication during childbirth and in the 48 hours postpartum period. Sudden cardiovascular collapse, air hunger, loss of consciousness and disseminated intramuscular coagulation are usual presentations. Acute pulmonary hypertension from arterial obstruction is complicated by the release of cytokines and complements that produce multisystem failure. Complement C3 and C4 are low in serum, and zinc coproporphyrin levels are elevated. There is no specific therapy for amniotic fluid embolism. Extracorporeal membrane oxygenation and correction of acidosis and other metabolic derailments are therapeutically maintained as well as possible under the circumstance. The pregnancy is terminated by C-section and the prognosis of the newborn is good. Air embolism happens in about 4 per 100,000 childbirths. The mortality is 60 to 80%.

 Embolisms are of several kinds and emboli can originate from various sources. Deep vein thrombosis resulting in pulmonary embolism is common among various groups and in a selected population, like nursing homes, cancer hospitals and ICU units, the incidence is high.

The current nursing practice of early mobilization following surgery, trauma, and childbirth has substantially lowered the incidence of PE. The direct acting anticoagulant improved patients' compliance with therapy.

  

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Arterio Venous Malformation

 

                                              Arteriovenous malformation

                                               PKGhatak, MD

In 2011, Mike Patterson, a prominent Philadelphia Eagles football player, had a seizure on the playing field. Later in the day, it was determined that Mike's seizure was due to an arteriovenous malformation in the brain. In the succeeding months, more known cases of arteriovenous malformation (AVM) in celebrities became known. It is estimated that 1 in every 100,000 world population has AVM, however, most of them did not have any symptoms.

AVM develops when the artery makes a direct path to the veins without first connecting with capillaries. AVM may arise in any place in the body, however, when present in the brain or spinal cord they tend to be symptomatic. When AVM in the brain enlarges, it produces pulsating pain, nausea, vomiting, and various neurological symptoms depending on the location and seizures. When AVM ruptures, it becomes a catastrophic event.

AVM is an inherited condition but also occurs due to somatic gene mutations, and occasionally following injuries and stab wounds. In some cases, AVM develops from cavitary pulmonary tuberculosis, schistosomiasis, and juvenile hepatic cirrhosis. It is a difficult task to determine the mode of inheritance in every case of AVM. There are about 600 mutations of genes associated with AVM. The well known Osler- Rendu- Weber syndrome or hereditary hemorrhagic telangiectasia (HHT) is due to autosomal dominant inheritance. The mutated genes are two:

 No1. Endigin gene mutation is present on chromosome 9.

 No 2. Activin receptor kinase gene mutation is present on chromosome 12.

Just one copy of one of the two mutated genes will manifest as HHT. The MADH4 gene mutation is associated with colon polyps and AVM. These genes are under the control of the RASA1 gene. In normal circumstances, the RASA1 gene transcribes a protein kinase controlling capillary formation. In HHT blood vessel developments are defective at several levels due to abnormal cytokine function.

At birth, most of the AVMs are small and may not be visible but as the child grows, the AVM enlarges and in adolescence, the enlargement accelerates. AVMs on the face, neck, and chest wall are often associated with visceral AVM. AVMs tend to grow for a period and then regress spontaneously, in some cases, continue to slow growth.

Besides AVM, congenital abnormalities of veins, capillaries and lymphatics are known. But the incidence of these abnormalities is less frequent.

Pulmonary AVM.

The AVM of the lung is usually small and remains asymptomatic. Multiple or larger AVMs are detected in chest x-rays. In rare instances, a large AVM occupies an entire lobe or two lobes of the lungs, called diffuse AVM. AVM of the lung is seen in 40% of hereditary hemorrhagic telangiectasia.

Pulmonary AVM usually produces recurrent hemoptysis, pneumothorax, hemothorax, recurrent pneumonia, septicemia and TB, and other infections. Large and diffuse AVM produces low oxygen saturation of the arterial blood (PaO2). Low PaO2 is due to pulmonary arterial blood, instead of going to the alveoli, drains directly into the pulmonary veins. A Right to Left shunt develops. Hypoxic symptoms arising from the brain, liver and kidneys begin early, and congestive heart failure is a late development.

Cerebro-spinal AVM.

AVM of the brain is present in 30% of HHT and about 1 % of AVM is located in the spinal cord. Most of these AVMs are symptomatic. Initially, the symptoms are mild and nonspecific - headache, seizures, visual or speech problems, balance and ambulation abnormalities. Any increase in the size of the AVM either due to growth or infection or bleeding/ clot formation produces a symptom depending on the location of the AVM. Visual field loss, diplopia, cranial nerve palsy, weakness of limbs or incoordination are usual symptoms. Pulsating noise in the head is a distinct symptom due to the rapid flow of blood from an artery to a vein. Infections and rupture of AVM are real possibilities. Rupture of AVM may be the first presenting symptom and such incidences are as high as 50%. Intense headaches and rapid onset of coma usually follow. If treatment is delayed, the outcome is bad. Infected emboli from the lung result in brain abscesses. Meningoencephalitis, high pressure hydrocephalus, seizures, cranial nerve palsy and hemiparesis are complications from the infection.

Renal and genitourinary AVM.

Hematuria, repeated UTI and vaginal bleeding and uterine infection in women are seen but less frequently.

Hepatic AVM.

Most of the AVMs are small and maybe multiple and remain silent. In HHT the incidence of hepatic AVMs is 40%. The chances of infection of AVM in the liver are high. Pain in the upper right quadrant of the abdomen is the presenting symptom. Infection of the liver, cholangiohepatitis, hepatic insufficiency, and intra-abdominal bleeding occur. Portal hypertension, esophageal varies and GI bleeding is seen.

Hereditary Hemorrhagic Telangiectasia.

HHT is an autosomal dominant hereditary disease, in North America, the incidence of HHT is 1 in 10,000 population. Mucocutaneous telangiectasia of lips is a distinct feature and is present in 95% of HHT. The bluish dilated venules of the lips and floor of the mouth and tongue are present at ages 10 to 20. Telangiectasia of the fingertips and chest wall develops in the 30s to 40s. Nose bleeding in HHT is a daily occurrence and leads to iron deficiency anemia and occasionally requires a blood transfusion.

Another feature of HHT is bleeding AVM from the stomach and small intestine. The GI bleeding may be massive. Hemoptysis and neurological symptoms develop from AVM of the lungs and brain respectively.

One word of caution – bronchoscopy or endoscopy procedures must be conducted with extreme care. Biopsy of tissue is strictly prohibited, once bleeding starts, the control of bleeding is nearly impossible except removal of the organ by immediate surgery.

Cutaneous AVM.

The port-wine stain of the face, chest wall, and other areas of the body is due to skin capillary AVM, often cutaneous AVM is associated with visceral AVM.

Diagnosis and Treatment.

Recurrent hemoptysis, GI, or genitourinary bleeding, when accompanied by cutaneous telangiectasia, diagnosis is not difficult. Most large sized pulmonary AVMs are symptomatic. Bluish discoloration of lips and fingers, clubbing of fingers and a distinct humming noise on chest auscultation, presence of right heart enlargement and congestive heart failure, features of neurological symptoms when present together, the clinical diagnosis is almost certain.

Imaging is very helpful. Contrast enhanced CT is very specific. MRI, Angio-CT and the new generation of Doppler Ultrasound scans have replaced most other diagnostic tools of the earlier days - like Bubble tests and Angiograms. In the bubble test, several microbubbles are injected on the venous side and microbubbles are detected by ultrasound scans of the arteries.

Controlling bleeding where possible is attempted first, but in most cases immediate embolization of the artery is necessary. Other therapeutic options are - sclerotherapy or laser coagulation. If non-surgical treatment to control bleeding fails, then surgery is the only option that remains. In cases of distressing nose bleeds, various forms of plastic surgery procedures are attempted to patch over the location of telangiectasia.

In HHT the family members are strongly encouraged to undergo genetic testing and counseling.

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6 Minute Walk Test.

 

                                                  Six-minute walking Test

                                                PKGhatak, MD

The six-minute walk test (6MWT) is a useful tool for the evaluation of cardiac, pulmonary, and musculoskeletal systems. The test is low tech and requires practically no tools - an even surface long corridor, a pulse oximeter, a few chairs to sit along the path, a stopwatch and a distance measuring wheel, all that is needed. A 30 meter (100 feet) long corridor is ideal, but a shorter corridor also serves well.

Why do the 6MWT test:

In previous generations, the cardiopulmonary reserve was evaluated by a maximum voluntary ventilation test. This test was more suited for Olympic prospects or astronauts. The expired air had to be collected while exercising and analyzed for oxygen consumption. 6MWT test does not require any gas collection. It allows the patient to walk at his own pace, may stop, sit down, and then may resume the test. Only the distance walked in 6 minutes is recorded. Pulse oximetry and a stopwatch are carried by the supervisor. The patient may wear the smartwatch to detect an abnormal heart rhythm.

Cardiac stress test vs 6MWT.

6MWT is a safe initial method to evaluate cardiac and pulmonary status following an adverse coronary event or a respiratory disease. 6MWT does not replace cardiac tests; it is a useful supplement.

How 6MWT is performed.

No preparation is necessary. The patient should wear a pair of comfortable shoes, should continue to use oxygen, if on oxygen, use at the same flow rate. Use a cane or walker if used to.  A 10 minute rest before the test begins is required. Attach the pulse oximeter to a fingertip. Then start walking when a signal is given by the test supervisor. Continue to walk at the same pace, sit and rest on a chair on the way, if required, then resume walking again. When 6 minutes are up, stop walking. The supervisor marks the end distance and the test is complete.

Interpretation of 6MWT.

The formula for men.

A normal 6-minute walk distance (6MWD) = 1140 m(meter) – 5.61 x  BMI(body mass index) – 6.94 x age of the patient.

To obtain the lowest normal distance, subtract 153 m.

The formula for females.

6MWD = 1017 m – 6.24 x BMI – 5.83 x age.

To obtain the lowest normal distance, subtract 139 m.

The patients' results are given as the distance in meters and also as a percentage of the normal.

The initial results are then used to monitor the progression of the disease, improvement of therapy, drop in oxygen saturation, hypotension, potential drop attacks, the onset of chest pain, etc.

Indication of 6MWT.

The ideal candidates for this test are -

1. Recent cardiac events, 2.Pulmonary atrial hypertension,3. Peripheral arterial disease, COPD in need of oxygen therapy 4. Frail patients suffering from chronic diseases requiring rehabilitation, 5. the elderly who want to live independently, and 6. anyone else who is starting cardiopulmonary rehab from an existing morbid condition.

What the test predicts.

The test indicates cardiac and pulmonary reserve capacities, response to therapy and long term prognosis of chronic illnesses.

What are the advantages of 6MWT:

6MWT is a simple but highly duplicable test. Situated for the elderly population suffering from Pulmonary arterial hypertension, peripheral arterial disease, or had an adverse cardiac event,

What are the contraindications:

The patient having an unstable cardiac arrhythmia should not do this test. Those who have experienced unexplained cardiovascular collapse and those in respiratory distress are not suitable for 6MWT.

edited: June 2025

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Hemoptysis

 

                                                             Hemoptysis

                                                    PKGhatak,MD

Hemoptysis was considered the confirmation of Consumption - a disease of the ancient world. Even if a patient was wasting away but did not have hemoptysis, the condition was called by something else than consumption. This practice went on till Dr. Robert Koch discovered a bacterium and demonstrated conclusively that the bacteria were responsible for the disease called consumption. Later on, that bacteria were named Mycobacteria tuberculosis and the disease is known as pulmonary tuberculosis (TB). Hemoptysis continued to be the primary symptom of TB patients. The incidence of hemoptysis began to fall in 1945 with the introduction of Streptomycin and Para-amino salicylic acid (PAS). And subsequently, fell further in 1954 onwards with the use of Isoniazid and Ethambutol.

Hemoptysis is defined as coughing up any amount of blood, the quantity of blood is not included in the definition. Massive hemoptysis is defined as losing 200 ml or more of blood, between 5 and 200 ml of blood loss is considered moderate, and anything 5 ml or less is considered as minimal hemoptysis.

It should be kept in mind that the trachea, bronchus and all its branches are supplied by the arteries of the systemic circulation. And because the systemic circulation operates at high pressure, the blood loss becomes massive in a very short period of time, if a moderate sized vessel wall is breached.

In every case of hemoptysis, details should be taken about nose bleeds, use of anticoagulants (blood thinners), antiplatelet agents, and history of aspiration, and history of blood disorders.

Common Causes of hemoptysis.

Inflammation/ infection of the trachea and bronchial tree accounts for 25 % of hemoptysis, Carcinoma of the lung and lung metastasis – 20%, Bronchiectasis - 10%, Cardiovascular and Pulmonary emboli - 10 %, lung contusion from automobile accidents and other conditions -35 %.

Reported causes of Hemoptysis: -

Lung cancer, narcotizing pneumonia, cystic fibrosis, COPD, pulmonary emboli/infraction, lung abscess, bronchiectasis, TB, fungal infection, pneumonic plague, sinusitis, acute bronchitis, bronchovascular fistula, congestive heart failure, bleeding diathesis, arteriovenous malformation, hereditary hemorrhagic telangectasia, endometrial tissue metastasis in lungs, bronchlolithiasis, mitral stenosis, severe pulmonary hypertension, pulmonary edema, Wegener granuloma, microscopic polyangiitis, aspergilloma, foreign bodies, Goodpasture syndrome, cocaine other recreational drug use, bronchoscopic biopsy, trauma to chest wall causing bruised lungs from automobile accidents, Anticoagulant and antiplatelet therapy.

Presenting symptoms.

Patients often experience a sensation of heaviness in the chest and something gurgling inside the chest before they cough up blood. The blood brought up may contain gritty broncholiths, blood and pus in cases of lung abscess. Recurrent hemoptysis is usual in TB and bronchiectasis patients. Streaks of blood and rusty sputum are present in bacterial pneumonia cases.

Diagnosis and Treatment.

Like any emergency situation - triage, quick assessment, securing a patent airway and prevention of aspiration, positioning the patient in bed with the involved side down, reassurance and relieving fear, is followed by tests and imaging.

In the case of massive hemoptysis, the initial attempt is made to control bleeding. If the patient's history does not suggest blood disorder or coagulation/platelet dysfunction, then an immediate bronchoscopy with rigid and fiberoptic bronchoscope is performed under general anesthesia. Localizing the source of bleeding is essential. If the bleeding site is detected, then the bleeding vessel is cauterized by laser or electro-cauterization or argon plasma coagulation. If the bleeding site is distal to the fiberoptic bronchoscope and the scope cannot be advanced further, then tamponade is achieved by radiopaque surgical dressings or by a balloon catheter.

After controlling bleeding, an Angio-CT is obtained. If the bleeding vessel is identified then embolization of the vessel is carried out. If that fails, then surgical excision of the lesion or lobectomy is required.

In a previous generation, hemoptysis from cavitary TB was successfully controlled by therapeutic pneumothorax. In rural communities of some poor countries, this treatment is still carried out. The therapeutic pneumothorax for the treatment of pulmonary TB in the 1910s was advanced by Dr. Carlo Forlanini of Italy. For his efforts he was nominated for the Nobel Prize in Medicine 20 times between 1912 and 1932; his sponsors were not discouraged because Dr. Robert Koch was nominated for the Nobel Prize in Medicine 50 times before he was awarded the Nobel Prize in 1905.

In a patient who is not actively bleeding, a CT of the chest is performed in the hope that localizing the disease would be possible; often CT is negative. Fiberoptic bronchoscopy is performed to detect cancer or any source of bleeding.

In cases of minimal but recurrent bleeding, the bleeding usually stops after 6 months. These patients are followed for cancer surveillance.

Bleeding from pulmonary hypertension and mitral stenosis, congestive heart failure, pulmonary edema, infectious causes, etc. are treated medically and supplemented by surgery where applicable.

Embolization of arteriovenous malformation is useful therapy. Recurrence of pulmonary emboli is treated with anticoagulant. All other treatable medical conditions are appropriately treated. 

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Bronchiectasis

Bronchiectasis

PKGhatak,MD

Bronchiectasis is a permanent dilatation of a small segment of the bronchial tube that results from the destruction of walls of the bronchus from repeated inflammation or infection.

Bronchiectasis due to cystic fibrosis accounts for 50% of all cases of bronchiectasis. Congeal or acquired deficient mucociliary defense mechanism, ciliary dyskinesia, alpha 1 antitrypsin deficiency, congenital mitochondrial diseases, congenital or acquired Immunoglobulin diseases, immunocyte depression from immunotherapy, etc. favor repeated bacterial, fungal, and mycobacterial infections. HIV infection and account for a few cases. Chronic lung diseases like pulmonary emphysema, silicosis, allergic aspergillosis, pulmonary tuberculous and foreign body bronchus, pulmonary fibrosis secondary to rheumatoid arthritis, Sjorgren syndrome, SLE, Crohn's disease, etc. accounts for the rest of cases of bronchiectasis.

Childhood infection and Bronchiectasis.

Measles and whooping cough are dominant causes of bronchiectasis in poor countries, equally important, post bacterial pneumonia, specially due to Staphylococcus aureus, Hemophilus influenza and pulmonary tuberculosis.

Bronchiectasis is a small pouch, as the mucus accumulates in the pouch, the mucus remains at the site. It is a favorable medium for bacteria, fungus, or mycobacteria growth. Repeated and/persistent infections damage the structure of the bronchus, erode blood vessels causing hemoptysis, or ruptures into the pleural space and develop an open path to the pleural space and produce a bronchopleural fistula and which can easily lead to a purulent pleural effusion and pleural fibrosis.

Descriptive types.

About 50% of bronchiectasis are cylindrical types, 40% are cystic, 10% are beaded - (narrow segments of structurally normal bronchi are interspersed between rows of the dilated portions). 25% are of mixed types.

Presenting symptoms.

Cough productive of a large volume of purulent sputum; when allowed settling, separates in three distinct layers -  the bottom consists of necrotic cells and tissues, the middle layer contains clear fluid and the top layer contains foaming surface. The sputum has a sweet offensive odor. Fever, loss of weight, malnutrition, etc. are due to chronic wasting conditions, but hemoptysis occurs frequently, the volume of blood brought up is generally moderate quantity, and rarely massive hemoptysis can exsanguinate the patient.

Kartagener Syndrome.

Kartagener syndrome is an autosomal recessive inherited disease. A patient presents with repeated sinusitis, bronchitis/pneumonia, hemoptysis, clubbing of fingers and toes and sterility in males. The defect is due to ciliary dyskinesia. Associated conditions are situs inversus of various degrees – from dextrocardia (heart and great vessels are on the right side) to a complete reversed position of all internal organs and the presence of bronchiectasis.

Diagnosis of Bronchiectasis.

A chest x-ray may or may not show any abnormality that is the specific radiological sign for bronchiectasis. CT of the chest, specially HTCT, shows the following signs – tram-lines (parallel lines with a clear central area), a bunch of grapes sign, signet ring sign, a string of pearl sign (narrow but intact bronchial segments in between small dilated bronchiectasis segments appear in a row). Location of positive radiological findings are in the - basal segments, right apical segments, left lingular segment and posterior upper middle segment.

Bronchoscopy.

All cases, at least initially, require bronchoscopic examination and are valuable to diagnose the presence of a foreign body bronchus, adenoma, carcinoma, or aspirated gastric contents and also to determine the degree of bronchiectasis involvement. Appropriate cultures, smears and cytology studies are routinely ordered.

Nowadays bronchograms are not performed. CT/ MRI eliminated that practice.

Pulmonary function impairment evaluations

Pulmonary function evaluations are carried out by PFT, oximetry, 6 mins walk tests and other appropriate tests to detect any and all underlying conditions that may lead to bronchiectasis.

Goal of treatment.

Depending on the underlying condition, the treatment and prognosis vary from one case to the other. A prompt and aggressive treatment protocol consists of proper antibiotic therapy, postural drainage of the retained bronchial secretion, chest percussion to help loosen thick sticky mucus, proper hydration of patients and the humidification of inhaled air.

Complications are minimized by antibiotic prophylaxis, bronchodilator drugs, mucolytic agents, appropriately administered pneumonia, influenza vaccines and surgical intervention when hemoptysis continues.

Surgery.

If the bronchiectasis is localized to one segment only, the lobectomy is only curative therapy, if the patient still has an adequate pulmonary reserve.

Bronchiectasis numbers are decreasing in developing countries because of good public health measures, childhood vaccination like MMR and adult vaccination programs and prompt medical attention to the needs of patients.

But the same cannot be said about poor countries and where people are forced to live in refugee camps.

Attempts should be made to limit the damage to the lungs by implementing good public health measures.

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