Crysis Hypertension - Urgency VS Emergency Hypertension

Hypertensive Crisis - Urgency VS Emergency

Introduction

Hypertensive Crisis is typically defined as Systolic Blood Pressure (SBP) > 220 mm Hg or Diastolic BP > 125 mm Hg. Basically, it was devided into 2 types :

• Hypertensive Urgencies
  
• Hypertensive Emergencies
  

Hypertensive Urgency

Hypertensive Urgency are situations in which Blood Pressure must be reduced within a few hours (<> 220 mmHg or DBP > 125 mmHg that persists after a period of observation) and without evidence of acute end-organ damage.

Hypertensive Emergency

Hypertensive Emergency are situations in which SBP > 220 mmHg or DBP > 125 mmHg and require substantial reduction of blood pressure within 1 hour to avoid the risk of serious morbidity or death.

Clinical Manifestation of Hypertensive Emergency :

• Eyes: Retinal hemorrhages and exudates, papilledema.
• CNS: Intracranial hemorrhage, lacunar infarcts, stroke, or hypertensive encephalopathy. The latter is characterized by the insidious onset of headache (often occipital and worse in the morning), nausea, and vomiting, followed by alterations in mental status, lethargy, and restlessness/agitation. Can progress to seizures and coma if untreated. Generally characterized by the lack of localizing neurologic signs.
• CV: Pulmonary edema, unstable angina/myocardial infarction, acute aortic dissection.
• Renal: Malignant nephrosclerosis, leading to acute renal failure, hematuria, and proteinuria. Activation of the renin-angiotensin system can further exacerbate the HTN.
• Hematologic: Hemolytic anemia can occur with severe HTN.

Others Type Of Hypertensive Emergency :

• Malignant Hypertension - In order to diagnose Malignant Hypertension, papilledema must be present
• Accelerated Hypertension - Defined as a recent significant increase over baseline blood pressure that is associated with target organ damage. This is usually vascular damage on funduscopic examination, such as flame-shaped hemorrhages or soft exudates, but without papilledema.
  

Treatment

Hypertensive Urgency

• Goal : To relieve symptoms and bring BP to reasonable level within 24–48 hours, aiming for gradual attainment of optimal control over several weeks
• Medication : Clonidine, Captopril, Metoprolol, and Hydralazine are effective oral agents.
• Precautions : Avoid B-Blockers if cocaine use, Avoid angiotensin-converting enzyme (ACE) inhibitors if renal artery stenosis suspected, Avoid short-acting dihydropyridine calcium channel blockers because BP reduction is often precipitous
  

Hypertensive Emergency

• Goal : To reduce mean arterial pressure by 25% in 1–2 h; then to reduce BP to 160/100 mm Hg over next 6–12 h
  
• Medication : Nitroprusside, labetalol, and nitroglycerin are most commonly used intravenously. Fenoldopam, a peripheral dopamine agonist, is also effective
• Precautions : If with ischemic stroke, only treat if BP exceeds 220/120 mm Hg; aim to reduce by only 10–15%, If thrombolytic agents are to be used to treat ischemic stroke, target BP is <>
• ACE inhibitors are specifically indicated in scleroderma crisis

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Mean Arterial Pressure (MAP)

Mean Arterial Pressure (MAP)

Definition

Mean arterial pressure is a term to describe a notional average blood pressure in an individual. It is defined as the average arterial pressure during a single cardiac cycle.

The blood pressure in our body is always changing and it is part of the human physiology. It is very rare that someone's blood pressure is always the same. Because we are always active and we are always doing different things like eating, sitting, standing, walking, breathing, moving around and doing so many other things throughout a day.

Formula

As blood is pumped out of the left ventricle into the arteries, pressure is generated. The mean arterial pressure (MAP) is determined by the Cardiac Output (CO), Systemic Vascular Resistance (SVR), and Central Venous Pressure (CVP) according to the following relationship, which is based upon the relationship between Flow, Pressure and Resistance :

MAP = (CO × SVR) + CVP

Because CVP is usually at or near 0 mmHg, this relationship is often simplified to:

MAP Approx = CO × SVR

Therefore, changes in either CO or SVR will affect MAP. If CO and SVR change reciprocally and proportionately, then MAP will not change. For example, if CO doubles and SVR decreases by one-half, MAP does not change (if CVP = 0). It is important to note that variables found in are all interdependent. This means that changing one variable changes all of the others.

In practice, MAP is not determined by knowing the CO and SVR, but rather by direct or indirect measurements of arterial pressure. From the aortic pressure trace over time, the shape of the pressure trace yields a mean pressure value (geometric mean) that is less than the arithmetic average of the systolic and diastolic pressures as shown to the right.

Why Measuring The MAP?

There are different reasons that mean arterial pressure is taken and recorded. Not all are related to health. The mean arterial pressure is known as part of a couple biological processes that do not show any health problems. When an arterial blood flow goes through the body it is going somewhere that it has in mind. Usually the blood is pumped through the arteries and left in the beds of capillaries that will run across the surface of different organs and give them the nutritional substances that are needed to operate properly.

Perfusion Pressure is Thought to Actually be The Mean Arterial Pressure.
MAP = Perfusion Pressure

For the mean arterial pressure to allow an organ to operate the way that it should, it must be at around 60 mmHg. This is enough for an organ of the average size person as long as it is remains at this spot. If the value falls below the average, it means that there is not enough blood pumping into the organ and this will cause the organ to become ischemic. The result will be tissue damage to the organ. The mean arterial pressure should be checked and calculated on a regular basis. Some health officials check the value of a person's arterial pressure when they check a person's blood pressure. It is just one of the many calculations that have to be made about blood pressure.

Simplyfied Mean Arterial Pressure (MAP) Equation

MAP = [(2 x Diastolic)+Systolic] / 3

Interpretation

• MAP around 70 - 110 : Normal

• MAP of about 60 : Necessary to Perfuse Coronary Arteries, Brain, Kidneys

• MAP less than 60 : Low Perfusion - Will Cause Ischemic Organ and Tissue Damage

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Prothrombin Time (PT) & International Normalize Ration (INR)

Prothrombin Time (PT) & International Normalize Ratio (INR)

Introduction

An INR is useful in monitoring the impact of anticoagulant (“blood thinning”) medicines, such as Warfarin(Coumadin). Patients with atrial fibrillation often take anticoagulant medications to protect against clots that can cause strokes. While taking Warfarin, patients have regular blood tests to monitor their INR. Just as patients know their blood pressure numbers, they also should know their Warfarin (Coumadin) dosage and their INR.

This standarization system was introduced by World Health Organization (WHO) in 1983 to provide a common basis for the interpretation of the PT result independent of the sensivity of the thromboplastin reagen which tends to vary from one manufacturer to another

Normal Result Of Prothombin Time

Although there is some variation depending on the source of the thromboplastin used in the test. (For this reason, laboratories report a normal control value along with patient results.) A prothrombin time within this range indicates that the patient has normal amounts of clotting factors VII and X.

The Normal Prothrombin Time (PT) is 11-15 seconds

Abnormal Results Of Prothombin Time

A prolonged PT time is considered abnormal. The prothrombin time will be prolonged if the concentration of any of the tested factors is 10% or more below normal plasma values. A prolonged prothrombin time indicates a deficiency in any of factors VII, X, V, prothrombin, or fibrinogen.

It may mean that the patient has a vitamin K deficiency, a liver disease, or disseminated intravascular coagulation (DIC). The prothrombin time of patients receiving warfarin therapy will also be prolonged-usually in the range of one and one half to two times the normal PT time. A PT time that exceeds approximately two and a half times the control value (usually 30 seconds or longer) is grounds for concern, as abnormal bleeding may occur.

Formula

INR = Patient PT / Mean Of Normal Patient Range

Interpretation (INR)

• 1.0 : For Healthy People,
• 2.0 - 3.0 : For patients on anticoagulants, or patients with atrial fibrillation,
• 3.0 - 4.0 : For patients with mechanical heart valves.
• > 4.0 : Indicate that blood is clotting too slowly (High Risk For Uncontrolled Bleeding)

The Ideal INR must be individualized for each patient

While the INR reporting format may improve the management of anti-coagulanted patient, the INR inapproriate in three subsets, such as :

1. The System was designed for patient who are stabilized on oral anticoagulant therapy and is not appropriate for those patient who have recently begun their treatment.
2. Patient with liver disease should not be monitored by the INR since they frequently lack circulating factors
3. Patient who are being routinely screened for clotting factors deficiencies.

Food & Drug Effects

Do not take any prescription or nonprescription medicines without first talking to the doctor who tracks your INR test results. Foods high in vitamin K, a natural blood-clotting factor, can alter an INR. Broccoli, lettuce, spinach and liver are all high in vitamin K. Doctors usually encourage patients to include these nutritious foods in a healthy diet. It is important, however, to consume a consistent amount of these foods and not drastically change eating habits. It is important to have follow up blood tests as scheduled by your doctor and to know your Warfarin (Coumadin) dosage and INR.

Many Food & Drugs Can Change The INR such as :
Aspirin, Ibuprofen, Antibiotics, Vitamin K, Brocolli, Lettuce, Spinach, and Birth Control Pills/Progesterone-Estrogen Combination Pills.

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How To Correct Hyponatremia ?

How To Correct Hyponatremia ?

Serum sodium concentration and serum osmolarity normally are maintained under precise control by homeostatic mechanisms involving stimulation of thirst, secretion of antidiuretic hormone (ADH), and renal handling of filtered sodium. Irreparable harm can befall the patient when abnormal serum sodium levels are corrected too quickly or too slowly.

Classification

• Mild Hyponatremia - Na 135-130mEq/L,
• Moderate Hyponatremia - Na 129-125mEq/L,
• Severe Hyponatremia - Na 124-120mEq/L
  
• Life Threatening - Na <>

Prehospital Care

Prehospital treatment is directed toward treatment of symptoms (eg, seizures, arrhythmias) in severely symptomatic patients; the underlying hyponatremia is unlikely to be recognized prior to evaluation in the ED.

Emergency Department Care

Formulas for the dose and rate of hypertonic saline are based on a sodium deficit and have not been prospectively studied. These formulas should only be used as a guideline, requiring frequent retesting of serum sodium level.

Administration of 3% NaCl should only be required in patients with severely symptomatic hyponatremia (eg, seizures) or potentially in patients with Serum Sodium Level of less than 110 mEq/L

Total Sodium Deficit

Na Deficit (mEq) = (Desired Na – Measured Na) X 0.6 X (Weight in Kilograms)

Correction of Hyponatremia Using 3% Saline

Volume of 3% Saline (L) = (Na Deficit)/513 mEq Na/L

The rate of correction of Chronic Hyponatremia should not exceed 0.5 mEq/L per hour.
The rate of correction of Acute Hyponatremia should not exceed 1 - 2 mEq/L per hour.

Sodium levels should not be corrected to above 120-130 mEq/L or increase by more than 12 mEq/L per day. However, if necessary, as with a patient with Hyponatremia-Induced Seizure or Agitated Confusion, the initial rate of correction can be rapid, provided that the final rate of correction does not exceed 15 mEq/L per 24 hours.

Time Needed For Hyponatremia Correction

Time Needed for Correction = (Desired Na – Measured Na)/0.5 mEq/L per hour

The Rate of Infusion of Hypertonic Saline

Rate = (Volume of 3% Saline)/(Time Needed for Correction)

Other Solution That Can Be Used

Lactated Ringers : Contains 130 mEq/L = 0.130 mEq/ml
0.9% NaCl : Contains 154 mEq/L = 0.154 mEq/ml
1.8% NaCl : Contains 380 mEq/L = 0.380 mEq/ml
3% NaCl : Contains 513 mEq/L = 0.513 mEq/ml

Other Concern

1. Stop therapy when serum sodium concentration approaches 120-130 mEq/L, symptoms resolve, or serum sodium concentration has increased by 15 mEq/L in 24 hours or less.
2. Furosemide increases excretion of free water and can be used (1 mg/kg) in conjunction with isotonic or hypertonic saline.
3. Once normal renal function is ascertained, try to normalize potassium levels prior to or concurrently with the correction of hyponatremia.
4. Monitor serum and urine electrolyte levels. Initially, recheck them in 2 hours, then at least every 4 hours until the patient's levels are stabilized.
5. Aggressive treatment of hyponatremia should always be weighed against the risk of inducing Osmotic Central Pontine Myelinolysis (CMP) / Osmotic Demyelination Syndrome.
   
6. Although rare, osmotic myelinolysis is a serious complication and can develop one to several days after aggressive treatment of hyponatremia. Typical features are Disorders of Upper Motor Neurons including Spastic Quadriparesis and Pseudobulbar Palsy, and Mental Disorders ranging from Confusion to Coma. The risk is increased in persons with hepatic failure, potassium depletion, large burns, and malnutrition.

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Classification Of Acute Renal Failure (Based On The Causes)

Classification Of Acute Renal Failure (Based On The Causes)

The causes of acute renal failure (ARF) are conventionally and conveniently divided into 3 categories : prerenal, renal, and postrenal.

• Prerenal ARF involves an essentially normal kidney that is responding to hypoperfusion by decreasing the glomerular filtration rate (GFR).

• Renal or intrinsic ARF refers to a condition in which the pathology lies within the kidney itself.

• Postrenal ARF is caused by an obstruction of the urinary tract. Acute tubular necrosis (ATN) is the most common cause of ARF in the renal category.

Prerenal ARF

Prerenal ARF represents the most common form of kidney injury and often leads to intrinsic ARF if it is not promptly corrected.

• Volume loss from GI, renal, cutaneous (eg, burns), and internal or external hemorrhage can result in this syndrome.

• Prerenal ARF can also result from decreased renal perfusion in patients with heart failure or shock (eg, sepsis, anaphylaxis).

• Special classes of medications that can induce prerenal ARF in volume-depleted states are angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which are otherwise safely tolerated and beneficial in most patients with chronic kidney disease.

• Arteriolar vasoconstriction leading to prerenal ARF can occur in hypercalcemic states, with the use of radiocontrast agents, nonsteroidal anti-inflammatory drugs (NSAIDs), amphotereicin, calcineurin inhibitors, norepinephrine, and other pressor agents.

• The hepatorenal syndrome can also be considered a form of prerenal ARF because functional renal failure develops from diffuse vasoconstriction in vessels supplying the kidney.

Renal or Intrinsic ARF

Structural injury in the kidney is the hallmark of Renal or Intrinsic ARF, and the most common form is acute tubular injury (ATN), either Ischemic or Cytotoxic. Frank necrosis is not prominent in most human cases of ATN and tends to be patchy.

• Intrarenal Vasoconstriction is the dominant mechanism for the reduced glomerular filtration rate (GFR) in patients with ATN. The mediators of this vasoconstriction are unknown, but tubular injury seems to be an important concomitant finding.
  

• Urine backflow and intratubular obstruction (from sloughed cells and debris) are causes of reduced net ultrafiltration. The importance of this mechanism is highlighted by the improvement in renal function that follows relief of such intratubular obstruction.
  

• Apart from the increase in basal renal vascular tone, the stressed renal microvasculature is more sensitive to potentially vasoconstrictive drugs and otherwise-tolerated changes in systemic blood pressure. The vasculature of the injured kidney has an impaired vasodilatory response and loses its autoregulatory behavior.

• A physiologic hallmark of ATN is a failure to maximally dilute or concentrate urine (isosthenuria). This defect is not responsive to pharmacologic doses of vasopressin. The injured kidney fails to generate and maintain a high medullary solute gradient because the accumulation of solute in the medulla depends on normal distal nephron function.
  

• Failure to excrete concentrated urine, even in the presence of oliguria, is a helpful diagnostic clue to distinguish prerenal from intrinsic renal disease, in which urine osmolality is less than 300 mOsm/kg. In prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg.

• Glomerulonephritis can be a cause of ARF and usually falls into a class referred to as rapidly progressive glomerulonephritis (RPGN). The pathologic correlation of RPGN is the presence of glomerular crescents (glomerular injury) on biopsy; if more than 50% of glomeruli contain crescents, this usually results in a significant decline in renal function. Although comparatively rare, acute glomerulonephritides should be part of the diagnostic consideration in cases of ARF.

Postrenal ARF

Mechanical obstruction of the urinary collecting system, including the renal pelvis, ureters, bladder, or urethra, results in obstructive uropathy or postrenal ARF.

• If the site of obstruction is unilateral, then a rise in the serum creatinine level may not be apparent due to contralateral renal function. Although the serum creatinine level may remain low with unilateral obstruction, a significant loss of GFR occurs, and patients with partial obstruction may develop progressive loss of GFR if the obstruction is not relieved. Causes of obstruction include stone disease; stricture; and intraluminal, extraluminal, or intramural tumors.

• Bilateral obstruction is usually a result of prostate enlargement or tumors in men and urologic or gynecologic tumors in women.

• Patients who develop anuria typically have obstruction at the level of the bladder or downstream to it.

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Acute Renal Failure (ARF) - Chronic Renal Insufficiency (CRI) - End Stage Renal Disease (ESRD)

Acute Renal Failure (ARF) VS Chronic Renal Insufficiency (CRI)
VS
End Stage Renal Disease (ESRD)

Acute Renal Failure (ARF)

This is kidney failure that happens rather suddenly, where something has caused the kidneys to shutdown. This may be due to infection, drugs (prescription, over-the-counter, recreational), traumatic injury, major surgery, nephrotoxic poisons, etc.

Emergency dialysis may be needed until the situation resolves and the kidneys begin functioning again (this might take a short time, or months, or it might be permanent). While more acute episodes are possible in the case of IgAN (we often refer to them as "flare-ups"), IgA nephropathy is a condition that mainly causes chronic renal insufficiency (CRI), not usually acute renal failure (ARF).

However, some people may experience spontaneously-reversing acute renal failure as well. The latter are cases where serum creatinine goes up dramatically but later returns to a more normal baseline. In such cases, dialysis may be needed until the condition improves. ARF in the context of IgAN is usually more associated with the person developing a flare-up of HSP.

Chronic Renal Insufficiency (CRI)

This is when a disease such as IgA nephropathy slowly and gradually destroys the filtering capacity of the kidneys. It is sometimes referred to as Progressive Renal Insufficiency, Chronic Kidney Disease or Chronic Renal Failure (CRF). This kind of damage cannot currently be repaired, and as such, it is Irreversible. A person may have chronic renal failure for many years, even decades, before dialysis or a kidney transplant become necessary.

Chronic renal insufficiency does not, by itself, mean complete shutdown of the kidneys, and a person with chronic renal insufficiency may still pass urine normally, and may have more than enough kidney function left for normal functioning of the body. Note that you cannot judge the efficiency of your kidneys by the amount of urine you produce. People with quite advanced renal insufficiency, and even people on dialysis may still produce a fair amount of urine. But this does not mean that the kidneys are filtering waste nor regulating serum electrolyte levels efficiently.

Chronic renal insufficiency itself causes more loss of kidney function. One important aspect of kidney disease is that, once a kidney is damaged by it to a certain degree, it continues to deteriorate even if the underlying kidney disease can or could be cured. This is commonly referred to as the Point of No Return (PNR).

Classification Of Chronic Renal Insufficiency

Early Chronic Renal Insufficiency (Stages 1 to 2)
Advanced Chronic Renal Insufficiency (Stages 3 to 4)

Late Chronic Renal Insufficiency (Stages 5) - ESRD

What happens is that the chronic renal insufficiency (CRI) continues to progress on its own, scarring of the glomeruli continues, and kidney function continues to gradually decline. It's possible that controlling blood pressure with an ACE inhibitor like Ramipril, or an Angiotensin II Receptor Blocker like Cozaar or Avapro may slow this progression of chronic renal insufficiency.

There is also beginning to be some evidence that the class of anti-cholesterol drugs called "Statins" (like Lipitor, for example) may help slow progression of CRI.

The point of no return is generally considered to be when serum creatinine reaches 2.0 mg/dl in U.S. measurements, or about 175 umol/L in international SI measurement.

End-Stage Renal Disease (ESRD)

As Chronic Renal Insufficiency continues and progresses, the person may eventually reach the point where it is considered to be End-Stage Renal Disease (ESRD) also known as Late Chronic Renal Insufficiency. It is at this stage that you are on the threshold of needing renal replacement therapy (any form of dialysis, or a kidney transplant).

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Chronic Kidney Disease Staging

CHRONIC KIDNEY DISEASE STAGING

Introduction

Chronic kidney disease occur whenever the glomerular filtration rate (GFR) is less than 60 mL/min/1.73 m2 for about 3 months, with or without kidney damage, for examples : pathologic abnormalities or markers of damage including (proteinuria or kidney stones).

Classification - Staging

There are five stages of chronic kidney disease based on the GFR (Cockcroft-Gault Formula) :

* Stage 1: Normal or increased GFR (>= 90 mL/min/1.73m2) with evidence of kidney damage.

The emphasis is on diagnosis, treatment and prevention of disease progression.

* Stage 2: Mildly decreased GFR (60-89 mL/min/1.73m2) with evidence of kidney damage.

There is still interest in diagnosis and treatment of the underlying cause but the emphasis is shifting towards prevention of disease progression.

* Stage 3: Moderately decreased GFR (30-59 mL/min/1.73m2).

The emphasis is still on preventing disease progression but the evaluation and treatment of complications are becoming more of an issue.

* Stage 4: Severely decreased GFR (15-29 mL/min/1.73m2).

The emphasis is generally on treating complications and preparing for dialysis or kidney transplantation.

* Stage 5: Very little GFR left (<15 ml/min/1.73m2).

Treating complications becomes increasingly difficult and dialysis is usually started at this point.

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The Cockcroft-Gault Formula - Creatinine Clearance Estimation (By Using GFR)

The Cockcroft-Gault Formula - Creatinine Clearance Estimation
(By Using GFR)

INTRODUCTION

The formula gives the Glomerular Filtration Rate, in ml/hour. In other words, it estimates the rate at which plasma ultrafiltrate is produced by the kidneys.

This is a quick and dirty estimate, and gives a good estimate only when creatinine clearance is stable. If the creatinine concentration is rising, applying this formula would be highly inaccurate.

For most purposes, however, the Cockcroft-Gault formula is the most common formula used by physicians to estimate creatinine clearance, and thus Glomerular Filtration Rate (ml/min/1.73 m2).

THE FORMULA

The Cockcroft-Gault Formula is Used to calculate Creatinine Clearance.

MEN : GFR = (140 - age) x Weight (kg) / (72 x serum creatinine(mg/dl)) X 1

WOMEN : GFR = (140 - age) x Weight (kg) / (72 x serum creatinine(mg/dl)) X 0.85

OR

MEN : GFR = (140 - age) x Weight (kg) / (72 x serum creatinine/88.6(mcmol/L)) X 1

WOMEN : GFR = (140 - age) x Weight (kg) / (72 x serum creatinine/88.6(mcmol/L)) X 0.85

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Naproxen Test

NAPROXEN TEST

Requirement

The patients were given Naproxen Sodium at 500 mg/tablet, one tablet every 12 hours p.c. for a total of 4 doses. Body temperature was taken orally every two hours prior.

Naproxen 500 mg/tablet Every 12 Hours P.C For 2 Days

Interpretation

Fever lysis after or within the time frame of drug administration was interpreted as suggestive of either a neoplastic condition or a connective tissue disease.
Nonresponse of the fever to the drug was taken to suggest an infectious condition.

Naproxen Administration was discontinued if any of the following were noted :

1). Hypersensitivity reaction,
2). Abdominal complaints, or
3). Patient refusal to take the drug.

Pathophysiology

Postulated pathogenic mechanisms for its occurrence include massive tumor necrosis, extensive neoplastic cell destruction, local inflammation due to ulceration of normal or malignant tissue, leucocytic infiltration of the neoplasm, interference with conjugation of pyrogenic steroids secondary to liver metastases and excessive heat production by tumor cells.

Neoplastic Fever is the second most common cause of fever in cancer patients after infection. The establishment of the etiology of fever in patients with malignancy however, remains to be a challenging diagnostic scenario for clinicians. Distinguishing between infectious fever and neoplastic fever is of paramount importance in cancer patients because of the urgency and necessity for appropriate treatment in these immunocompromised hosts.

The more recent mechanism involves induction of pyrogenic cytokines such as tumor necrosis factor, interleukins 1 and 6 and interferon by the tumor cells itself or by host macrophages in response to the tumor. Cytokines stimulate production of prostaglandin E2 which act on the hypothalamus causing a change in the thermostatic set point. Naproxen is a non-steroidal anti-inflammatory drug which acts as an inhibitor of cyclooxygenase. It has been demonstrated to have both analgesic and antipyretic effects.

Subsequent observational studies on small groups of patients with specific malignancies similarly
had promising results, but likewise suffered from this critical flaw. This precluded further estimation of the sensitivity, specificity and likelihood ratios of the naproxen test. It is suggested that the more appropriate reference standard would be the absence of infection after extensive and thorough laboratory work-up coupled with the absence of any clinical deterioration without administration of any antibiotics on continued follow-up for at least a period of 2 weeks. Specifically, the more convincing evidence that a patient does not have any infection despite extensive work-up would be the non-deterioration of the patient in the absence of any antibiotics during a prolonged follow-up period.

With the advent of modern diagnostic technology, it is timely that the usefulness of this
test be re-evaluated in the present decade. In the Philippines, it is best that this test be validated in a tertiary center with a laboratory and radiology department that is equipped with highly sensitive diagnostic and imaging procedures that are needed to rule out any infection from bacterial, viral, fungal or parasitic etiology. Likewise the staff should be competent in the performance and interpretation of these procedures.

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Creatinine and Creatinine Clearance

Creatinine and Creatinine Clearance

Creatinine and creatinine clearance tests measure the level of the waste product creatinine in your blood and urine. These tests tell how well your kidneys are working. The substance creatine is formed when food is changed into energy through a process called metabolism. Creatine is broken down into another substance called creatinine, which is taken out of your blood by the kidneys and then passed out of your body in urine.

Creatinine is made at a steady rate and is not affected by diet or by normal physical activities. If your kidneys are damaged and cannot work normally, the amount of creatinine in your urine goes down while its level in your blood goes up.

Three types of tests on creatinine can be done:

Blood Creatinine Level

The blood creatinine level shows how well your kidneys are working. A high creatinine level may mean your kidneys are not working properly. The amount of creatinine in the blood depends partly on the amount of muscle tissue you have; men generally have higher creatinine levels than women.

Creatinine Clearance Test

A creatinine clearance test measures how well creatinine is removed from your blood by your kidneys. A creatinine clearance test gives better information than a blood creatinine test on how well your kidneys are working. A creatinine clearance test is done on both a blood sample and on a sample of urine collected over 24 hours (24-hour urine sample).

Blood Urea Nitrogen-to-Creatinine ratio (BUN:creatinine)

The levels of blood creatinine and blood urea nitrogen (BUN) can be used to find the BUN-to-creatinine ratio. A BUN-to-creatinine ratio can help your doctor check for problems, such as dehydration, that may cause abnormal BUN and creatinine levels.

Urea is a waste product made when protein is broken down in your body. Urea is made in the liver and passed out of your body in the urine. A blood urea nitrogen (BUN) test measures the amount of urea in your blood. Like creatinine, it can help your doctor see how well your kidneys are working.

Why It Is Done?

A blood creatinine level or a creatinine clearance test is done to:

* See if your kidneys are working normally.
* See if your kidney disease is changing.
* See how well the kidneys work in people who take medicines that can cause kidney damage.
* See if severe dehydration is present. Dehydration generally causes BUN levels to rise more than creatinine levels. This causes a high BUN-to-creatinine ratio. Kidney disease or blockage of the flow of urine from your kidney causes both BUN and creatinine levels to rise.

How To Prepare?

Do not do any strenuous exercise for 2 days (48 hours) before having creatinine tests.

Do not eat more than 8oz of meat, especially beef, or other protein for 24 hours before the blood creatinine test and during the creatinine clearance urine test.

It is important to drink enough fluids during the 24-hour urine collection but do not drink coffee and tea. These are diuretics that cause your body to pass more urine.

Collection of The Blood Sample & The 24-Hour Urine Sample

* Blood Sample will be taken by the Medical Proffesional - then will be examined in the Laboratory for the Blood Creatinin Level.
* After that, you can start collecting your urine in the next morning. When you first get up, empty your bladder but do not save this urine. Write down the time that you urinated to mark the beginning of your 24-hour collection period.
* For the next 24 hours, collect all your urine. Your doctor or lab will usually provide you with a large container that holds about 1 gal (4 L). The container has a small amount of preservative in it. Urinate into a small, clean container and then pour the urine into the large container. Do not touch the inside of the container with your fingers.
* Keep the large container in the refrigerator for the 24 hours.
* Empty your bladder for the final time at or just before the end of the 24-hour period. Add this urine to the large container and record the time.
* Do not get toilet paper, pubic hair, stool (feces), menstrual blood, or other foreign matter in the urine sample.

Results

Creatinine and Creatinine Clearance Tests measure Creatinine Levels in your Blood and Urine to give information about how well your kidneys are working. The creatinine clearance value is found from the amounts of creatinine in the urine and blood and from the amount of urine you pass in 24 hours. This value is the amount of blood cleared of creatinine per minute, based on your body size. Below are the normal range of the Blood Creatinine, Creatinine Clearance & BUN To Creatinin Ratio :

Blood Creatinine:

Men : 0.6–1.2 milligrams per deciliter (mg/dL) or 53-106 micromoles/L (mcmol/L)
Women : 0.5–1.1 mg/dL or 44–97 mcmol/L
Teen 0.5–1.0 mg/dL
Child 0.3–0.7 mg/dL
Newborn 0.3–1.2mg/dL

Creatinine Clearance:

Men 90–140 milliliters per minute (mL/min) or 1.78–2.32 milliters per second (mL/sec)
Women 87–107 mL/min or 1.45-1.78 mL/sec
Creatinine clearance values normally go up as you get older (normal values go down by 6.5 mL/min for every 10 years past the age of 20).

BUN-To-Creatinine Ratio

Over 12 months of age: 10:1–20:1

Infants less than 12 months of age: Up to 30:1

INTERPRETATION

High values

* High creatinine blood levels. High creatinine blood levels can mean serious kidney damage or disease is present. Kidney damage can be caused by a life-threatening infection, shock, cancer, or low blood flow to the kidneys. Other conditions that can cause high blood creatinine levels include blockage of the urinary tract (such as by a kidney stone), heart failure, dehydration, excessive blood loss that causes shock, gout, or muscle conditions (such as rhabdomyolysis, gigantism, acromegaly, myasthenia gravis, muscular dystrophy, and polymyositis). Usually a high blood creatinine level means that the creatinine clearance value is lower than normal.
* High creatinine clearance. High creatinine clearance values can be caused by strenuous exercise, muscle injury (especially crushing injuries), burns, carbon monoxide poisoning, hypothyroidism, and pregnancy.
* High BUN-to-creatinine ratio. High BUN-to-creatinine ratios occur with sudden (acute) kidney failure, which may be caused by shock or severe dehydration. A blockage in the urinary tract (such as a kidney stone) can cause a high BUN-to-creatinine ratio. A very high BUN-to-creatinine ratio may be caused by bleeding in the digestive tract or respiratory tract.

Low Values

* Low blood creatinine levels. Low blood creatinine levels can mean lower muscle mass caused by a disease, such as muscular dystrophy, or by aging. Low levels can also mean some types of severe liver disease or a diet very low in protein. Pregnancy can also cause low blood creatinine levels.
* Low creatinine clearance. Low creatinine clearance levels can mean serious kidney damage is present. Kidney damage can be from conditions such as a life-threatening infection, shock, cancer, low blood flow to the kidneys, or urinary tract blockage. Other conditions, such as heart failure, dehydration, and liver disease (cirrhosis), can also cause low creatinine clearance levels.
* Low BUN-to-creatinine ratio A low BUN-to-creatinine ratio may be associated with a diet low in protein, a severe muscle injury called rhabdomyolysis, pregnancy, cirrhosis, or syndrome of inappropriate antidiuretic hormone secretion (SIADH). SIADH sometimes occurs with lung disease, cancer, diseases of the central nervous system, and the use of certain medications.

What Affects the Test

Reasons you may not be able to have the test or why the results may not be helpful include:

* Taking medicines, such as methyldopa (Aldomet), trimethoprim (Proloprim, Trimpex), vitamin C (ascorbic acid), cimetidine (Tagamet), some diuretics, and cephalosporin antibiotics, especially cefoxitin (Mefoxin). These affect the blood creatinine levels.
* Taking medicines, such as vitamin C (ascorbic acid), phenytoin (Dilantin), some cephalosporin antibiotics, captopril, aminoglycosides (Garamycin), trimethoprim (Proloprim, Trimpex), cimetidine (Tagamet), quinine, quinidine (Cardioquin, Quinaglute, Quinidex), procainamide, and the antifungal medication amphotericin B. These affect the creatinine clearance levels.
* Taking medicines, such as cimetidine (Tagamet), steroids, and tetracycline antibiotics. These can affect the BUN-to-creatinine ratio.
* Doing strenuous exercise 2 days before creatinine clearance test.
* Eating more than 8oz of meat, especially beef, in the 24 hours before a blood creatinine test and during a creatinine clearance urine test.

What To Think About

* A high blood creatinine level is generally seen with a low creatinine clearance level because creatinine in the blood is removed by the kidneys. If the kidneys are not able to remove creatinine (low creatinine clearance), levels of creatinine in the blood go up (high blood creatinine level).
* If you are pregnant, your doctor can check the amount of creatinine in amniotic fluid to see how developed, or mature, your baby's kidneys are. This can be helpful if there is a chance your baby will be delivered early. A baby who has mature kidneys will make more creatinine than a baby whose kidneys are still developing.
* A normal blood creatinine level does not rule out kidney disease. To help see whether kidney damage may be present, a BUN level is also measured. Other tests may also be done to check for kidney disease. For more information, see the medical test Blood Urea Nitrogen.
* Creatinine levels increase more slowly than blood urea nitrogen (BUN) levels, so an increase in creatinine may mean chronic kidney problems.
* A glomerular filtration rate may be done for people with chronic kidney disease to regularly check how well the kidneys are working.
* Diabetes experts recommend that blood creatinine levels be done every year for people with diabetes. The creatinine level is used to find the glomerular filtration rate, which shows how well the kidneys are working.
* The amount of creatinine in the blood depends partly on the amount of muscle tissue; blood creatinine levels are generally higher in men than in women. Also, people who have large muscles, such as athletes, normally have above-average blood creatinine levels.
* A one-time urine sample to measure urine creatinine and sodium is sometimes done along with blood creatinine and sodium levels to help find the fractional excretion of sodium (FENA). This test can help your doctor see whether a problem with blood flow to the kidneys is caused by dehydration or shock or by damage to the kidneys themselves.

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Diuretic Induced Hypokalemia

DIURETIC INDUCED HYPOKALEMIA

INTRODUCTION

Hypokalemia is a relatively common problem with diuretic therapy. Profound hypokalemia (serum potassium concentrations ≤2.5 to 3.0 meq/L), however, is relatively rare, described in fewer than 10 to 15 percent of patients receiving high doses of diuretics, and generally only in those not receiving potassium supplementation.

The decrease in plasma concentration following prolonged administration of 50 mg of hydrochlorothiazide per day is approximately 0.5 meq/L, whereas the same dose of long-acting chlorthalidone causes a greater fall in serum potassium concentration (0.8 meq/L) [1] . In contrast, short-term administration (three days) of 50 mg of chlorthalidone and 40 mg of furosemide results in a fall in serum potassium concentration of only 0.4 and 0.2 meq/L, respectively.

The incidence and severity of hypokalemia are dose-dependent, occurring much less frequently with lower doses [5,6] . Thus, lower doses of thiazides (eg, 12.5 mg/day of hydrochlorothiazide or chlorthalidone) or loop diuretics are now widely used in the treatment of hypertension because they are as effective in blood pressure reduction with a lesser effect on electrolyte balance.

MECHANISMS

Two factors appear to be responsible for the urinary potassium wasting :

• Increased delivery of sodium and water to the aldosterone-sensitive potassium secretory site in the collecting tubules; and

• Increased secretion of aldosterone due to diuretic-induced volume depletion or due to an underlying disease such as heart failure (show figure 3) [7] .

TIME COURSE

In stable patients on a fixed diuretic dose, potassium loss, like other diuretic-induced fluid and electrolyte complications, occurs only during the first two weeks of therapy before a new steady state is established. Thus, a stable patient with a normal serum potassium concentration at three weeks is not at risk of late hypokalemia unless the diuretic dose is increased, extrarenal potassium losses increase, or dietary potassium intake is reduced.

CLINICAL SIGNIFICANCE

The development of hypokalemia is of greatest concern in patients with underlying heart disease, cirrhosis, or hypertension:

* Potassium depletion can lead to cardiac arrhythmias, particularly in the presence of concurrent digitalis therapy or a serum potassium concentration ≤3.0 meq/L [1] . In addition, hypokalemia may contribute to an increased incidence of sudden death in patients with hypertension and left ventricular hypertrophy.

* Hypokalemia (serum potassium less than 3.5 meq/L) can precipitate hepatic coma in some patients with advanced cirrhosis, due at least in part to increased renal ammonia synthesis. The latter effect is mediated in part by a transcellular potassium-hydrogen exchange.

* Potassium depletion may have two additional deleterious effects in patients with hypertension: it can raise the blood pressure by a mean of 5 to 7 mmHg (probably due in part to concurrent sodium retention); and it can increase the incidence of stroke, independent of other cardiovascular risk factors. On the other hand, potassium supplementation can lower the blood pressure by an average of 6/3 mmHg.

TREATMENT

All patients treated with a diuretic should be monitored for the development of hypokalemia during the first two to three weeks of therapy. In stable patients on a fixed dose of a diuretic (eg, for hypertension), potassium loss occurs only during the first two to three weeks of therapy before a new steady state is established.

Once a steady state is reached, further monitoring is not required, unless the diuretic dose is increased, extrarenal potassium losses increase, or dietary potassium intake is reduced. As an example, increased losses and decreased intake may be seen with gastroenteritis. In such patients, temporary cessation of diuretic therapy for a few days may be appropriate.

The best way to treat diuretic-induced hypokalemia is prevention by using the lowest effective dose. Not surprisingly, the risk of hypokalemia (as well as other diuretic-induced metabolic complications) is dose-dependent. Therapeutic issues vary with the underlying condition being treated.

Hypertension — In most hypertensive patients, 12.5 to 25 mg of hydrochlorothiazide (or its equivalent) produces as great a fall in blood pressure as higher doses, but a much smaller reduction in the serum potassium concentration.

The frequent lack of improved blood pressure control with higher diuretic doses may be related to activation of the renin-angiotensin-aldosterone system: angiotensin II is a potent vasoconstrictor that will tend to counteract the antihypertensive effect of more fluid loss, while hyperaldosteronism will enhance urinary potassium losses.

Low-dose thiazide therapy is not generally used in patients with resistant hypertension, underlying renal insufficiency, or an edematous state. Loop diuretics are preferred in the latter two settings. (See "Optimal dosage and side effects of loop diuretics" and see "Resistant hypertension").

Given the typically small reduction in serum potassium with low-dose thiazide therapy, prophylactic therapy to avoid hypokalemia is not warranted. If hypokalemia does occur, there are two main options: switch to another antihypertensive drug; or treat the hypokalemia with potassium chloride supplements (beginning with 40 meq/day) or with a potassium-sparing diuretic such as amiloride, triamterene, or spironolactone. Among the potassium-sparing diuretics, we prefer amiloride because it has the fewest side effects.

Potassium-sparing agents also spare magnesium [1,9,11] . This is a desirable effect since diuretic-induced magnesium depletion may be directly arrhythmogenic and may also cause hypokalemia that is refractory to potassium repletion alone.

Correction of hypokalemia has the added advantage of producing a small further reduction in blood pressure

Heart failure and cirrhosis — Prophylactic therapy to prevent hypokalemia is an important issue in patients with heart failure and cirrhosis:

* Among patients with heart failure, hypokalemia may precipitate serious arrhythmias. It is recommended that the serum potassium concentration be maintained between 4.0 and 5.0 meq/L. In addition, hyperaldosteronism itself appears to contribute to adverse cardiac events in patients with moderate to severe heart failure due to mineralocorticoid receptors in the heart and vasculature. In such patients, outcomes may be improved with a mineralocorticoid receptor antagonist (spironolactone or eplerenone) (show figure 5). Thus, patients who need chronic therapy for a below goal serum potassium concentration should be treated with a mineralocorticoid receptor antagonist rather than potassium supplements.

The data supporting the cardiac and vascular toxicity of hyperaldosteronism are discussed separately. (See "Use of diuretics in heart failure", section on Improved survival with aldosterone antagonism, and see "Clinical features of primary aldosteronism", section on Cardiovascular risk).

* Among patients with cirrhosis, hypokalemia can promote the development of hepatic encephalopathy, perhaps in part by increasing ammonia production. The serum potassium concentration should be maintained above 3.4 meq/L. Most patients with cirrhosis are already being treated with spironolactone, since it is part of the recommended diuretic regimen. (See "Initial therapy of ascites in patients with cirrhosis", section on Concerns with diuretic therapy and section on Diuretic regimen).

As mentioned above, potassium-sparing agents also spare magnesium [1,9,11] . This is a desirable effect since diuretic-induced magnesium depletion may be directly arrhythmogenic and may also cause hypokalemia that is refractory to potassium repletion alone. (See "Signs and symptoms of magnesium depletion").

PROPHYLAXIS

A separate issue from potassium replacement is the possible role of prophylactic potassium supplementation in patients with heart failure who need aggressive diuresis and have a borderline serum potassium concentration (eg, 4.0 to 4.2 meq/L since the goal is to maintain the serum potassium at a minimum of 4.0 meq/L). There are two approaches in such patients: more frequent monitoring, which we prefer, or prophylactic potassium supplementation.

MONITORING

After initiation of either potassium-sparing diuretics or potassium supplements, potassium levels must be monitored. As with the development of hypokalemia, the rise in the serum potassium concentration with a fixed dose of either potassium chloride or a potassium-sparing diuretic in a stable patient will generally be complete within the first two to three weeks of treatment. Ongoing periodic monitoring is required in patients with heart failure or cirrhosis, who may have progressive disease.

SUMMARY AND RECOMMENDATIONS

Hypokalemia is a relatively common problem with diuretic therapy, with the risk increasing at higher doses. Marked hypokalemia (serum potassium concentrations ≤2.5 to 3.0 meq/L) is uncommon, being described in fewer than 10 to 15 percent of patients receiving high doses of diuretics.

The development of hypokalemia is of greatest concern in patients with underlying heart failure or cirrhosis, as it may lead to arrhythmias and hepatic coma, respectively. In addition, it may lead to a modest elevation in blood pressure in hypertensive patients.

In patients with hypertension who develop diuretic-induced hypokalemia, either another agent can be used, or the hypokalemia can be treated with a potassium-sparing diuretic or potassium supplementation. If a potassium-sparing is chosen, we suggest amiloride, as it has the fewest side effects.

In patients with heart failure or cirrhosis who develop hypokalemia on diuretic therapy, therapy should include a mineralocorticoid receptor antagonist since these drugs are used for reasons other than hypokalemia:

* In patients with heart failure, we recommend a mineralocorticoid receptor antagonist (spironolactone or eplerenone) because of improved survival due in part to blockade of mineralocorticoid receptors in the heart and vasculature (Grade 1B).

Such benefits of mineralocorticoid receptor blockade have not been evaluated in patients with essential hypertension in whom hyperaldosteronism is not a typical feature. However, mineralocorticoid receptor blockers are important in patients with primary aldosteronism.

* We recommend a mineralocorticoid receptor antagonist (spironolactone or, if not tolerated, eplerenone) in patients with cirrhosis and ascites due to increased diuretic efficacy compared to amiloride (Grade 1B).

After initiation of potassium sparing agents or potassium supplements, potassium levels should be monitored, particularly during the first two to three weeks of treatment and after dose adjustments.

Diuretic-induced hypokalemia is best prevented by use of the lowest effective dose.

We suggest not routinely providing prophylactic therapy to prevent hypokalemia (Grade 2C). This is particularly true in patients with hypertension on low-dose thiazide therapy. Patients with heart failure who are undergoing a rapid diuresis require more frequent monitoring of the serum potassium concentration.

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Clinical Manifestation of Peptic Ulcer Disease

CLINICAL MANIFESTATION OF

PEPTIC ULCER DISEASE

INTRODUCTION

Peptic ulcers may present with a wide variety of symptoms, or may be completely asymptomatic, sometimes until complications such as hemorrhage or perforation occur. Many patients complain of upper abdominal discomfort, but these symptoms are not specific and the differential diagnosis is broad.

CLINICAL MANIFESTATIONS

A pragmatic definition of "dyspepsia" is when the clinician suspects that symptoms are coming from the upper GI tract. Dyspepsia occurs in three common patterns:

• Ulcer-Like or Acid Dyspepsia (eg, burning, epigastric hunger pain with food, antacid, and antisecretory agent relief)
  

• Indigestion (also called functional dyspepsia or dysmotility-like dyspepsia, with postprandial belching, bloating, epigastric fullness, anorexia, early satiety, nausea, and occasional vomiting); and
  

• Reflux-Like Dyspepsia.
  

These patterns overlap considerably. Although the clinical assessment is critical for overall management, it has poor predictive value for the specific diagnosis found upon the endoscopy.

The "classic" symptoms of duodenal ulcer (DU) occur when acid is secreted in the absence of a food buffer. Food is usually well emptied by two to three hours after meals, but food-stimulated acid secretion persists for three to five hours; thus, classic ulcer symptoms occur two to five hours after meals or on an empty stomach. Symptoms also occur at night, between 11 PM and 2 AM, when the circadian stimulation of acid secretion is maximal. The ability of alkali, food, and antisecretory agents to produce relief suggests the role of acid in this process. Thus, "acid dyspepsia" is a fitting term. Gastric ulcer (GU) has classically been associated with more severe pain occurring soon after meals, with less frequent relief by Antacids or food.

Discomfort occurs in the epigastrium in about two-thirds of symptomatic patients, but may occasionally localize to the right or left upper quadrants or the hypochondrium. Radiation of pain to the back may occur, but primary back pain is atypical. Although ulcer pain is often burning, gnawing, or hunger-like in quality, the discomfort can be vague or cramping. Symptomatic periods lasting a few weeks followed by symptom-free periods of weeks or months is a pattern characteristic of classic DU.

However, dyspeptic symptoms are neither sensitive nor specific. Thus, reliance upon the presence of these symptoms alone to make the diagnosis of peptic ulcer will result in overdiagnosis of patients who have nonulcer dyspepsia and will miss the diagnosis in some patients who have peptic ulcers. In one study, for example, a self-report questionnaire examined the three common dyspeptic symptom patterns. Ulcer-like dyspepsia was most common, but 43 percent of the subjects with dyspepsia could be classified into more than one subgroup, suggesting that the history alone had a poor discriminant value for determining the etiology. Several other studies have indicated that only 15 to 25 percent of patients presenting with typical acid dyspepsia have underlying peptic ulcer disease.

The classic symptoms of acid dyspepsia with food relief, described above, occur in only about 50 percent of patients with a DU. Approximately 20 percent report an increase in appetite or weight gain, while many others have a stomach that is "irritable" to food, other chemicals, or mechanical distention, resulting in indigestion, anorexia, weight loss, and fatty food intolerance. Heartburn occurs in 20 to 60 percent of patients with DU, and symptoms typical of irritable bowel syndrome (eg, crampy, periumbilical abdominal pain related to altered bowel function and often relieved by decompressing the colon) are also common.

Silent ulcers — In a study from Taiwan, 11 percent of 6457 subjects undergoing screening endoscopy had a peptic ulcer of whom 70 percent were asymptomatic. In addition, 20 to 50 percent of complicated ulcers present without heralding symptoms; this "silent" presentation is more frequent in elderly patients and individuals consuming nonsteroidal antiinflammatory drugs (NSAIDs).

Pathogenesis of ulcer pain — The mechanism by which peptic ulcers cause symptoms is unclear. At least a portion of patients with DU develop symptoms when acid bathes the ulcer crater. This was demonstrated in a randomized, double-blind study of 40 patients with DU which found that 16 (40 percent) developed typical acid pain upon bathing the ulcer through the endoscope with 0.1 N hydrochloric acid, while only 4 (10 percent) complained of pain with saline. In comparison, hydrochloric acid infusion into the duodenum did not produce pain in patients without DU.

However, the pain experienced by patients with peptic ulcers reflects factors more complex than acid bathing an ulcer crater. The secretory rates and concentration of acid in symptomatic patients overlaps with that found in asymptomatic patients and in controls. In addition, there is often no correlation between the presence of an active ulcer (as shown by endoscopy) and symptoms. As many as 40 percent of patients with healed ulcers (as shown by endoscopy) have persistent symptoms, while 15 to 44 percent of those who become symptom-free still have an ulcer crater at endoscopy.

Thus, the disappearance of symptoms does not guarantee ulcer healing, nor does the persistence of symptoms consistently predict the presence of an ulcer crater. For reasons that are not explicable, some patients perceive acid bathing their gastroduodenal mucosa, while others do not. In some cases this sensitization to acid is related to the presence of an ulcer crater or to the secretion of excess acid, but it may occur in the face of grossly normal mucosa and with physiologic levels of acid secretion.

Ulcer complications — The majority of complications, especially in the absence of NSAID use, are associated with chronic peptic ulcers, which are surrounded by fibrosis and have been presumably smoldering for months or longer. NSAID ulcers sometimes lack surrounding fibrosis and are presumably acute, developing and complicating over the first days or weeks of NSAID use. Similarly, stress ulcers developing in the ICU setting can be acute, without surrounding fibrosis. Complications may be heralded by new ulcer symptoms or a change in symptoms or may occur in the absence of typical symptoms ("silent" ulcers).

• Penetrating ulcers classically present with a shift from the typical vague visceral discomfort to a more localized and intense pain that radiates to the back and is not relieved by food or Antacids.

• The sudden development of severe, diffuse abdominal pain may indicate perforation.

• Vomiting is the cardinal feature present in most cases of pyloric outlet obstruction.

• Hemorrhage may be heralded by nausea, hematemesis, melena, or dizziness.

• Gastrocolic fistula, a very rare complication, can present with halitosis, feculent vomiting, postprandial diarrhea, dyspepsia, and sometimes weight loss.

Many patients underestimate the significance of their symptoms and fail to present in a timely fashion.

NSAID-induced ulcers — Although NSAIDs can cause dyspepsia and peptic ulcers, there is frequently a dissociation between symptoms and pathology. As an example, one study evaluated the appearance of the gastroduodenal mucosa in 65 patients treated with a variety of NSAIDs for at least six consecutive weeks to treat osteoarthritis or rheumatoid arthritis. Dyspeptic symptoms were more common in patients with a completely normal endoscopy (19 versus 9 percent in those with an abnormal endoscopy). In addition, only 3 of the 10 patients with ulcers had dyspeptic symptoms. In contrast, dyspepsia appearing during a controlled trial of NSAID treatment in high risk patients has been observed to predict ulcer recurrence. Thus, although one can expect frequent dissociation between symptoms and ulcers, the development of gastrointestinal symptoms in a patient taking NSAIDs is an important clue to an underlying ulcer and should prompt evaluation.

Atypical ulcers — A number of atypical presentations of peptic ulcer may occur.

Giant ulcers — Most peptic ulcers are less than 1 to 2 cm in diameter; ulcers more than 2 cm in diameter are termed giant ulcers. Giant DUs are usually located on the posterior wall. They may present with a prolonged typical history, pain radiating to the back, or few, if any, symptoms. Reversible anorexia and weight loss can be observed in the absence of malignancy.

Giant ulcers are frequently complicated by bleeding and posterior penetration and, depending on location, by pyloric obstruction. One study, comparing 62 patients with giant gastric ulcers (defined as ≥3 cm) to 476 patients with smaller gastric ulcers, found that the giant ulcers were more prone to severe hemorrhage (44 versus 27 percent) and penetration into contiguous organs (45 versus 10 percent). In addition, the risk of microscopic malignancy in the macroscopically benign giant ulcer was significantly higher (13 versus 3 percent). Other studies have also confirmed that malignancy is more frequent in giant compared to smaller ulcers. In one report, the presence of a visible vessel in the ulcer crater predicted the clinical course of giant duodenal ulcers; 7 of 15 patients with a visible vessel required eventual operation, compared to only 1 of 13 patients without a visible vessel.

There are some conflicting data regarding demographics and risk factors associated with giant ulcers, which probably reflect the time frame and population under investigation. In one study, giant ulcers occurred more frequently in older subjects and in association with NSAID consumption. However, in another study Methamphetamine or Cocaine use, as well as NSAIDs, were major risk factors (the odds ratio for stimulant use was 9.7). This latter study also found that giant ulcers were inversely related to patient age, possibly indicating that demographics of drug users may have influenced the outcomes.

Comorbidities appear to be an important contributing factor in the development of giant ulcers. Giant duodenal or prepyloric ulcers have been reported in association with end-stage renal failure, orthotopic lung transplantation, and Crohn's disease. The ulcer symptoms may be the presenting complaint in patients with Crohn's disease. Mechanisms were not defined, but are probably include poor nutrition, decreased mucosal blood flow, and poor healing.

H. pylori is certainly an important factor in some giant ulcers, but no prospective, controlled studies have examined its prevalence. Of the 23 patients who underwent antral biopsy in one study, only 9 were positive for H. pylori, suggesting the importance of other factors, such as NSAID use and comorbid conditions that predispose to ulceration.

Giant ulcers also heal more slowly and relapse more frequently than smaller ulcers, especially in patients with comorbid conditions. Medical management should include three elements: detection and treatment of H. pylori, if present; aggressive investigation to detect NSAID use and their discontinuation since healing is very difficult with continued use; and use of PPIs.

Pyloric channel ulcers — Ulcers located in the pyloric channel may be associated with pain occurring shortly after eating, poor relief by, Antacids and vomiting, the latter sometimes reflecting pyloric obstruction or dysfunction. Juxtapyloric ulcers, which occur at or within 2 cm of the pylorus, often present with complications. In one series, for example, patients with pyloric channel ulcers were more likely to undergo surgery than those with ulcers in the duodenal bulb.

Postbulbar ulcers — Duodenal ulcers are generally located in the duodenal bulb within 2 to 3 cm of the pylorus. Ulcers distal to the duodenal bulb (postbulbar ulcers) were found in 10 percent of cases in a necropsy series, but in only 15 of 4016 radiographic examinations. Ulcers beyond the second portion of the duodenum and into the proximal jejunum are characteristic of a gastrinoma and possibly other hypersecretory states. In one report of patients with gastrinoma, 75 percent of ulcers were in the first portion of the duodenum, 14 percent in the distal duodenum, and 11 percent in the jejunum.

No clinical features clearly distinguish postbulbar ulcers, although a higher rate of complications has been reported. The differential diagnosis includes diverticulae, adhesive bands, annular pancreas, and neoplasia of the pancreas and duodenum.

Multiple ulcers — Multiple simultaneous ulcers occur in 2 to 20 of patients with peptic ulcer. In one series, multiple DUs were associated with a higher male to female ratio, more patients with a late-onset (ulcer symptoms starting after age 30 years), chronic cigarette smoking, and moderate to severe deformity of the duodenal bulb. Multiple ulcers are often clustered together, suggesting that local pathogenic mechanisms, which involve compromised mucosal resistance to injury or impaired healing, are important for the development of this entity. NSAID use and gastrinoma should also be considered when multiple ulcers are encountered.

DIFFERENTIAL DIAGNOSIS — Peptic ulcer must be differentiated from other disorders that cause symptoms in the upper abdomen and ulcerative lesions of the stomach and duodenum that are secondary to diseases involving the gastroduodenal mucosal itself. The specific causes of ulcerative lesions of the stomach and duodenum must be identified whenever possible, since effective therapy is available for many cases secondary to other specific causes. Some of these conditions can be diagnosed by gross and histologic assessment of the gastric mucosa and are described below. In addition, a variety of other conditions are associated with PUD, which may or may not be detectable by biopsy or visual inspection.

Functional dyspepsia — The most common type of dyspepsia encountered in primary care and gastroenterology practice is functional (idiopathic) dyspepsia, also referred to as nonulcer dyspepsia. Although developed by an international committee for research purposes, the following definition of functional dyspepsia (Rome criteria) has clinical utility :

"Chronic or recurrent abdominal pain or discomfort centered in the upper abdomen; a duration of ≥one month with symptoms 25 percent of the time (ie, on seven days or more). No clinical, biochemical, endoscopic or ultrasonographic evidence of any known organic disease that is likely to explain the symptoms (ie, acid-peptic or neoplastic disease of the stomach, esophagus or duodenum, or disease of the pancreas or hepatobiliary system), and no history of major gastric or intestinal surgery. Patients with a past history of documented chronic peptic ulcer disease should not be classified as having functional dyspepsia at least until the relationship between these entities is clarified."

There are no diagnostic tests for functional dyspepsia, and it is difficult to distinguish ulcer from nonulcer dyspepsia on the basis of the clinical examination. As a result, the diagnosis is made upon the exclusion of other causes of dyspepsia.

Gastric carcinoma — It is important to differentiate between gastric carcinoma and peptic ulcer at an early stage, when the cancer is operable and potentially curable. Gastric malignancy infrequently causes chronic dyspepsia. However, the possibility should be considered, particularly in patients over 45 to 55 years of age and in those who have the following "alarm symptoms:"

• Unintended weight loss
• Bleeding
• Anemia
• Dysphagia
• Odynophagia
• Hematemesis
• A palpable abdominal mass or lymphadenopathy
• Persistent vomiting
• Unexplained iron deficiency anemia
• Family history of upper gastrointestinal cancer
• Previous gastric surgery
• Jaundice

Although early gastric cancer is usually asymptomatic, it can present with dyspepsia that is indistinguishable from peptic ulcer. A new onset of symptoms or a recent change in pattern are the usual flags that raise concern over possible neoplasia. In general, compared to advanced disease, early gastric cancer has fewer associated symptoms and a much better prognosis.

A review of published studies noted the following incidence of symptoms in European patients with early gastric cancer :

• Epigastric pain and/or dyspepsia, similar to peptic ulcer disease — 65 to 90 percent
• Nausea and/or vomiting — 6 to 40 percent
• Anorexia — 12 to 40 percent.

Warning (or alarm) signs or symptoms suggestive of invasive disease, such as anemia or weight loss, occurred less frequently (5 to 15 percent and 4 to 40 percent, respectively).

Other neoplastic lesions — Other neoplastic processes can mimic peptic ulcers, presenting with dyspepsia or ulcers, such as gastric lymphoma; leiomyosarcoma; primary gastric and metastatic, malignant melanoma; and metastatic renal cell carcinoma.

Drug-induced dyspepsia — Numerous drugs can cause dyspepsia, epigastric distress, nausea, or vomiting. These include NSAIDs, with or without ulceration, Theophylline, and Digitalis. Caffein, Coffee, Alcohol, and Smoking can also contribute to symptoms.

Infiltrative or granulomatous diseases — Infiltrative or granulomatous diseases can present with dyspepsia and occasionally ulceration. Involvement of the stomach is the most common site of sarcoidosis in the gastrointestinal tract, almost always occurring in association with pulmonary disease. Ulceration resembling peptic ulcer disease can occur with or without enlargement of mucosal folds. Eosinophilic granuloma and Wegener's granulomatosis can also present in this fashion.

Hypertrophic gastritis (including Menetrier's disease) may present with dyspeptic symptoms.

Crohn's disease — Crohn's disease may involve the stomach or duodenum and produce symptoms and a radiographic appearance which mimics peptic ulcer. Isolated gastroduodenal Crohn's is uncommon; radiographic abnormalities are usually present in more distal portions of the duodenum and the small intestine.

Infections — Gastric and duodenal tuberculosis involving the mucosa can present with ulceration. The diagnosis is generally difficult to make since superficial biopsies do not detect caseating granulomata, which are often submucosal, and the acid-fast stain may be negative. Thus, a high level of suspicion is necessary.

Other infections have also been associated with chronic ulcer:

• Mycobacterium avium intracellulare.

• Strongyloidiasis can produce upper abdominal pain and nausea; in addition, gastric ulcer with bleeding has been reported with infiltration in the ulcerated mucosa.

• Giardiasis may produce upper abdominal discomfort, nausea, and anorexia; these symptoms are often associated with diarrhea and occasionally evidence of malabsorption. Dyspeptic symptoms may persist over months, interspersed with periods of diarrhea lasting a few days.

Duodenal neoplasia — Duodenal carcinoma is very uncommon, but can occasionally present with gastrointestinal bleeding or as an apparently benign ulcer. However, most cases present as a mass lesion rather an ulcer. Localized duodenal lymphoma can also mimic duodenal ulcer and respond to therapy for a period of time.

Miscellaneous — A large number of disorders have been associated with peptic ulcer disease.

SUMMARY

• Peptic ulcers may present with a wide variety of symptoms, or may be completely asymptomatic, sometimes until complications such as hemorrhage or perforation occur. Many patients complain of upper abdominal discomfort, but these symptoms are not specific and the differential diagnosis is broad.

• The "classic" symptoms of duodenal ulcer (DU) occur when acid is secreted in the absence of a food buffer. Food is usually well emptied by two to three hours after meals, but food-stimulated acid secretion persists for three to five hours; thus, classic ulcer symptoms occur two to five hours after meals or on an empty stomach. Symptoms also occur at night, between 11 PM and 2 AM, when the circadian stimulation of acid secretion is maximal. The ability of alkali, food, and antisecretory agents to produce relief suggests the role of acid in this process. Thus, "acid dyspepsia" is a fitting term. Gastric ulcer (GU) has classically been associated with more severe pain occurring soon after meals, with less frequent relief by Antacids or Food.
  

• Discomfort occurs in the epigastrium in about two-thirds of symptomatic patients, but may occasionally localize to the right or left upper quadrants or the hypochondrium. Radiation of pain to the back may occur, but primary back pain is atypical. Although ulcer pain is often burning, gnawing, or hunger-like in quality, the discomfort can be vague or cramping. Symptomatic periods lasting a few weeks followed by symptom-free periods of weeks or months is a pattern characteristic of classic DU.

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