Alkalosis describes a condition in which there is an excess amount of base or alkali in the body fluids and tissues.
Presentation
The manifestations of this condition are linked to the patient's history such as in cases with vomiting or diarrhea. Also, electrolyte deficiencies are associated with specific clinical features. For example, hypokalemia results in weakness, polyuria, myalgia, and serious sequelae such as cardiac arrhythmias while hypocalcemia produces remarkable findings that include altered mental status, tetany, Trousseau sign, Chvostek sign, and possibly seizures. Additionally, volume changes are characterized by signs of dehydration such as orthostatic hypotension, dry mucous membranes, decreased urine output, etc.
The symptoms reflect the etiology, duration of the alkalosis, and its degree. Hyperventilation leads to acute hypocapnia, which in turn decreases cerebral perfusion. Therefore, patients experience confusion, lightheadedness, loss of consciousness, and seizures. Also, patients with hyperventilation syndrome develop dyspnea, chest pain, paresthesia, and tetany [7].
Common features on the exam include tachypnea, tachycardia, and arrhythmias. Signs of hypocalcemia may also develop [8].
Patients with chronic respiratory alkalosis do not usually exhibit symptoms.
Entire Body System
- Weakness
[…] acids and weak bases will resist changes in pH, thus acting as buffers Buffering is very important in biological systems, for rapid pH changes have disastrous consequences. [www2.csudh.edu]
[…] noun Medicine An excessively alkaline condition of the body fluids or tissues that may cause weakness or cramps. ‘Hypochloremic, hypokalemic, or metabolic alkalosis might be present in patients who purge.’ [en.oxforddictionaries.com]
Concomitant hypokalaemia may cause weakness. [pathology.leedsth.nhs.uk]
[…] into the categories of respiratory alkalosis and metabolic alkalosis or a combined respiratory/metabolic alkalosis.[1] Signs and symptoms[edit] Metabolic alkalosis is usually accompanied by low blood potassium concentration, causing, e.g., muscular weakness [en.wikipedia.org]
- Pain
If pain is causing the person to breathe rapidly, relieving the pain usually suffices. When respiratory alkalosis is caused by anxiety or a panic attack, a conscious effort to relax and slow breathing may make the condition disappear. [merckmanuals.com]
[…] disease, history of asthma, history of COPD, acute focal neurological signs, numbness, paresthesia, abdominal pain, nausea, vomiting, tinnitus, or weight loss. [ncbi.nlm.nih.gov]
Symptoms of respiratory alkalosis may include: anxiety chest pain lightheadedness muscle stiffness numbness around the mouth tremors Respiratory alkalosis may resemble the symptoms pneumonia, acute respiratory distress syndrome, and sepsis, among others [medicalnewstoday.com]
If your rapid breathing is caused by pain, then treating the pain will help bring your respiratory rate back to normal and improve your symptoms. [healthline.com]
- Fatigue
‘When this occurs, it may result in a state of alkalosis which can cause conditions from weakness and fatigue to headaches and anxiety.’ ‘These data suggest that hypocapnic but not metabolic alkalosis impairs alveolar fluid reabsorption.’ [en.oxforddictionaries.com]
However, most people experience nausea, vomiting and fatigue (feeling tired and weak.) You may also start to breathe deeper and faster. These symptoms can get worse the longer you experience acidosis. [mainlinehealth.org]
He described general weakness and fatigue the previous night and on waking, with no history of headaches, diarrhea, fevers, or other symptoms of infection. [aacc.org]
Acidosis may not cause any symptoms or it may be associated with nonspecific symptoms such as fatigue, nausea and vomiting. [labtestsonline.org.au]
~volume depletion ~ vomiting An 24-year-old woman is brought to the physician with a 3-month history of weakness and fatigue. [quizlet.com]
- Hypoxemia
Increased alveolar ventilation secondary to: Disorders causing acidosis Hypoxemia or Nonphysiologic stimulation of those receptors by CNS or chest disorders Rarely life threatening with pH typically <7.50 Metabolic alkalosis: Primary increase in serum [emergency.unboundmedicine.com]
On admission to hospital arterial blood gas results (pH 7.59, HCO3 45 mmol/L, pCO2 6.39 kPa, base excess +20.4 mmol/L and pO2 7.08 kPa) allowed a diagnosis of severe metabolic alkalosis and hypoxemia. [acutecaretesting.org]
This explains his elevated PCO 2 and respiratory acidosis that, in turn, explains his hypoxemia. Case Index>> Top of Page [courses.washington.edu]
Hypoxemia, as a result of progressive hypoventilation, eventually activates oxygen-sensitive chemoreceptors; the latter stimulates ventilation and limits the compensatory pulmonary response. [openanesthesia.org]
Sepsis (fever) (often before metabolic acidosis) DT, anxiety, pain DKA and aspirin OD Environmental HYPERthermia (Heat tetany) Drugs Aspirin OD Progesterone Liver failure (encephalopathy) with hyperammonaemia (ammonia) Iatrogenic (mechanical ventilation) Hypoxemia [lifeinthefastlane.com]
- Asymptomatic
Some affected individuals are asymptomatic, but others may be more severely affected, with growth problems and, not uncommonly, joint problems, tetany, and/or other neuromuscular abnormalities. [jci.org]
However, patients with classic Bartter's syndrome (type 3) present later in life and may be sporadically asymptomatic or mildly symptomatic. [patient.info]
Bicarbonate levels <40 mM are typically asymptomatic. [emcrit.org]
Although acknowledging that definitive evidence is lacking, we have indicated a series of thresholds at which it was felt that surgery could reasonably proceed in asymptomatic and otherwise uncomplicated patients. [academic.oup.com]
Typical manifestations range from asymptomatic biochemical disturbances to severe salt wasting leading in early life and may be complicated by renal failure. [intechopen.com]
Gastrointestinal
- Overeating
His sister reported that he had become more withdrawn over the past few weeks during which time his diet comprised only Pepsi and alcohol. [acutecaretesting.org]
A state characterized by a decrease in the hydrogen ion concentration of arterial blood below the normal level, 40 nmol/L, or pH over 7.4. [medical-dictionary.thefreedictionary.com]
Although ventilatory defects can cause significant increases in the Blood pH, renal compensatory mechanisms can largely correct the pH over several days. [pathwaymedicine.org]
Although acidosis is more common at ICU admission, bicarbonate increases over time (Figure 1 D) [ 3 ]. Alkalosis can be pure or mixed. [ccforum.biomedcentral.com]
- Constipation
The initial diagnosis was severe dehydration secondary to vomiting (probably induced by opiates and related constipation). [pmj.bmj.com]
They had poor appetites, and one had a history of constipation. All were hypochloremic and hypokalemic, with varying degrees of alkalosis and microhematuria. The 3 infants were taking the same brand of soy-based formula. [cdc.gov]
Constipation: prolonged retention of feces, resulting in increased amounts of HCO 3 – being reabsorbed. Excessive aldosterone: (adrenal tumors) promotes excessive reabsorption of Na +, which pulls increased amount of H + into urine. [amy47.com]
Chronic dehydration frequently causes constipation. A small muscle mass and muscle wasting are frequently seen in patients following a late diagnosis or in untreated patients. [emedicine.medscape.com]
- Abdominal Pain
In the past 4 months he had experienced intermittent generalized abdominal pain, nausea, anorexia, vomiting, and mild weight loss (3 kg). He had presented 2 months earlier with vomiting. [aacc.org]
Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis. [ 8 ] Other features include: Short stature. [patient.info]
He had no abdominal pain or focal symptoms and took no other medications. His past medical history included two similar admissions with vomiting, dehydration, hypokalaemia, and hyponatraemia. [pmj.bmj.com]
[…] disease, history of asthma, history of COPD, acute focal neurological signs, numbness, paresthesia, abdominal pain, nausea, vomiting, tinnitus, or weight loss. [ncbi.nlm.nih.gov]
Cardiovascular
- Hypotension
Additionally, volume changes are characterized by signs of dehydration such as orthostatic hypotension, dry mucous membranes, decreased urine output, etc. [symptoma.com]
Chloride-resistant alkalosis Causes of chloride-resistant alkalosis can be divided into those associated with hypertension and those associated with hypotension or normotension. [emedicine.medscape.com]
Physical exam findings may be just as varied depending on etiology to include fever, tachycardia, tachypnea, diaphoresis, hyper or hypotension, altered mental status, productive or non-productive cough, wheezing, rales, crackles, cardiac murmur or arrhythmia [ncbi.nlm.nih.gov]
Inhibitors of the renin–angiotensin system are often used, although their use can be limited by hypotension, especially in younger patients. [academic.oup.com]
- Heart Rate Irregular
Rapid heart rate, irregular heart beats, and a drop in blood pressure are also symptoms. Severe cases can lead to convulsions and coma. Diagnosis Metabolic alkalosis may be suspected based on symptoms, but often may not be noticeable. [encyclopedia.com]
Musculoskeletal
- Muscle Cramp
People may have irritability, muscle twitching, muscle cramps, or even muscle spasms. Blood is tested to diagnose alkalosis. [merckmanuals.com]
[…] pain, and muscle cramps (from disturbed function of the skeletal muscles), and muscle spasms (from disturbed function of smooth muscles). [en.wikipedia.org]
Muscle cramps and a lot of production of lactic acid from working out, can also increase in acidity. Anything that increases the number of carbon dioxide or carbonic acid in the blood leads to acidosis. [fmss12ucheme.wordpress.com]
- Muscle Twitch
People may have irritability, muscle twitching, muscle cramps, or even muscle spasms. Blood is tested to diagnose alkalosis. [merckmanuals.com]
Muscle twitching. Nausea, vomiting. Numbness or tingling in the face, hands, or feet. Prolonged muscle spasms (tetany) [studykorner.com]
twitching, and myoclonus and may be partly due to decreased serum ionised calcium concentrations.3 Chvostek’s sign is usually negative.4 Symptoms of muscle twitching and tetany appear to be more common than myoclonus. [pmj.bmj.com]
- Carpopedal Spasm
He was described as having “locked hands and curled toes” consistent with carpopedal spasms and twitching movements of his tongue. He had no focal neurological signs, and his power and reflexes were essentially normal. [aacc.org]
spasm Shift 02 dissociation curve to the left (Alkalosis) (Increased affinity of Hb for O2) Correction Treat underlying cause Re-breather mask References and Links Acid-Base: ABG analysis – Anion Gap – SID – NAGMA Metabolic acidosis: Overview – evaluation [lifeinthefastlane.com]
spasm Type 1 Excludes hysterical tetany ( F44.5 ) neonatal tetany ( P71.3 ) parathyroid tetany ( E20.9 ) post-thyroidectomy tetany ( E89.2 ) alkalosis E87.3 ICD-10-CM Codes Adjacent To E87.3 E85.9 Amyloidosis, unspecified E86 Volume depletion E86.9 Volume [icd10data.com]
Paresthesias, carpopedal spasm. Hypoventilation (due to respiratory compensation for the metabolic alkalosis). Generally not a significant issue. [emcrit.org]
These associated electrolyte abnormalities can also cause carpopedal spasms, muscle weakness, and altered mental status. Consultations Depending upon the primary etiology of the alkalosis, consultation may be necessary with various subspecialties. [ncbi.nlm.nih.gov]
Urogenital
- Renal Function Impairment
Milk-Alkali syndrome Ingestion of large amount of milk and absorbable antacids: CaCO3 Patient excrete large amount of Ca and HCO3 in the urine Ca deposits more in alkaline urine Deposition of Ca leads to renal function impairment Thus HCO3 increased [slideshare.net]
Neurologic
- Seizure
Shock It is important to recognize that in the case of seizures and shock, it is actually the accumulation of lactic acid that is responsible for the development of the elevated anion gap acidosis. [pulmonaryschools.com]
Therefore, patients experience confusion, lightheadedness, loss of consciousness, and seizures. Also, patients with hyperventilation syndrome develop dyspnea, chest pain, paresthesia, and tetany. [symptoma.com]
‘Serious complications include systemic hypokalemic alkalosis, leading to cardiac arrhythmias, renal damage, and seizures.’ [en.oxforddictionaries.com]
[…] oxyhaemoglobin dissociation curve Cardiovascular consequences: Decreased cardiac output due to decreased contractility Arrhythmias Neurological consequences Neuromuscular overexcitability Decreased cerebral blood flow due to cerebral vasoconstriction Seizures [derangedphysiology.com]
More severe alkalaemia increases protein binding of ionized Ca + +, leading to hypocalcaemia and subsequent headache, lethargy, and neuromuscular excitability, sometimes with delirium, tetany, and seizures. [pathology.leedsth.nhs.uk]
- Dizziness
You are dizzy, confused, or lose consciousness. You have a seizure. Care Agreement You have the right to help plan your care. Learn about your health condition and how it may be treated. [drugs.com]
Symptoms of Diabetic Metabolic Alkalosis Symptoms of diabetic metabolic alkalosis include: light-headedness and dizziness; nausea and vomiting; mental confusion; numbness or tingling in the face and extremities; muscle weakness; myalgia; muscle cramps [battlediabetes.com]
Symptoms of respiratory alkalosis may include muscle spasms, irritability, dizziness, and nausea. Respiratory alkalosis is one possible classification of an acid-alkaline imbalance in the body. [medicalnewstoday.com]
Patients may experience: Dizziness Confusion Loss of consciousness Muscle cramps or spasms Abnormal heart rhythms How is it diagnosed? The doctor will ask questions about the patient's health, perform a physical exam, and order blood tests. [symptoma.com]
Call 911 or go to the nearest emergency room if you experience any of these symptoms: dizziness difficulty breathing confusion stupor coma The symptoms of alkalosis mimic symptoms of other conditions. [healthline.com]
- Paresthesia
Alkalosis may cause Irritability Muscle twitching and cramps Tingling in the fingers and toes and around the lips Tingling (paresthesia) is a common complaint in hyperventilation due to anxiety. Sometimes alkalosis causes no symptoms at all. [merckmanuals.com]
Also, patients with hyperventilation syndrome develop dyspnea, chest pain, paresthesia, and tetany. Common features on the exam include tachypnea, tachycardia, and arrhythmias. Signs of hypocalcemia may also develop. [symptoma.com]
[…] confusion, light-headedness, dizziness, anxiety, chest pain, wheezing, hemoptysis, trauma, history of central line catheter, recent surgery, history of thromboembolic disease, history of asthma, history of COPD, acute focal neurological signs, numbness, paresthesia [ncbi.nlm.nih.gov]
Paresthesias, carpopedal spasm. Hypoventilation (due to respiratory compensation for the metabolic alkalosis). Generally not a significant issue. [emcrit.org]
- Headache
‘When this occurs, it may result in a state of alkalosis which can cause conditions from weakness and fatigue to headaches and anxiety.’ ‘These data suggest that hypocapnic but not metabolic alkalosis impairs alveolar fluid reabsorption.’ [en.oxforddictionaries.com]
More severe alkalaemia increases protein binding of ionized Ca + +, leading to hypocalcaemia and subsequent headache, lethargy, and neuromuscular excitability, sometimes with delirium, tetany, and seizures. [pathology.leedsth.nhs.uk]
He described general weakness and fatigue the previous night and on waking, with no history of headaches, diarrhea, fevers, or other symptoms of infection. [aacc.org]
The first clues that you are experiencing acidosis are a headache and sleepiness. [study.com]
Acute acidosis may also cause an increased rate and depth of breathing, confusion and headaches, and it can lead to seizures, coma, and in some cases death. [labtestsonline.org.au]
- Convulsions
Three years later the child, who did not have history of gastroesophageal reflux or epileptic convulsions, suddenly died during sleep. The cause of death could not be determined through gross examination of the body. [ncbi.nlm.nih.gov]
Severe metabolic alkalosis that is left untreated will lead to convulsions, heart failure, and coma. [encyclopedia.com]
Workup
Clinical assessment consists of a detailed history including that of medication use, a full physical exam, and the appropriate studies.
Metabolic alkalosis
The key tests include arterial blood gas (ABG) and a complete metabolic panel to evaluate electrolytes, renal function, etc. If the diagnosis is inconclusive, then the urinary chloride concentration should be measured.
On ABG, a pH greater than 7.45 indicates alkalemia. If the PaCO2 level is below 35 mm Hg, this reveals a respiratory origin. Also, acute episodes reveal a reduction in bicarbonate levels.
A complete blood cell count (CBC) must be obtained to investigate if sepsis is present. Furthermore, the clinician should obtain cultures of blood, urine, and sputum to rule out infection.
Further tests such as complete metabolic panel and screening for salicylate and theophylline should be performed.
Other diseases associated with hyperventilation should be excluded. Hence, a chest x-ray is crucial to evaluate underlying lung pathologies. Moreover, computerized tomography (CT) studies are obtained if radiography findings are unclear or if lung disease needs to be evaluated further.
Serum
- Hypercapnia
Hypercapnia is usually the result of hypoventilation rather than of increased CO2 production. [accessmedicine.mhmedical.com]
Patients who present with hypoxaemia and hypercapnia may be diagnosed with respiratory failure if the association with metabolic alkalosis is not appreciated. [ld99.com]
Low Urine Chloride Gastrointestinal causes Vomiting Nasogastric suction Chloride-wasting Diarrhea Villous adenoma of colon Renal Causes Diuretic use ( Urine Chloride >10 meq/L) Poorly reabsorbable anion Carbenicillin Penicillin Sulfate Phsophate Post-Hypercapnia [fpnotebook.com]
10 meq/L) 소화기관(Gastrointestinal causes) Vomiting Nasogastric suction Chloride-wasting Diarrhea Villous adenoma of colon 신장(Renal Causes) Diuretic use (Urine Chloride >10 meq/L) Poorly reabsorbable anion Carbenicillin Penicillin Sulfate Phsophate Post-Hypercapnia [clinicclinic2.cafe24.com]
Sepsis Hepatic failure Heat exhaustion Metabolic alkalosis: Chloride depletion: GI losses: Vomiting Nasogastric (NG) suctioning High-output ileostomy loss Chloride-losing diarrhea (villous adenoma) Renal loss: Diuretics (loop and thiazide) Post (chronic) hypercapnia [emergency.unboundmedicine.com]
- Bicarbonate Increased
If the primary disorder is acute respiratory acidosis, bicarbonate increases by 1 unit above 24 mEq/L for every 10 units of increase in pCO2 above a baseline of 40 mm Hg; If the primary disorder is acute respiratory alkalosis, bicarbonate decreases by [amboss.com]
Although acidosis is more common at ICU admission, bicarbonate increases over time (Figure 1 D) [ 3 ]. Alkalosis can be pure or mixed. [ccforum.biomedcentral.com]
Retention/Addition of Bicarbonate Several etiologies lead to increases in bicarbonate within the blood. The simplest of which is an overdose of exogenous sodium bicarbonate in a medical setting. [ncbi.nlm.nih.gov]
ABG in Metabolic Alkalosis Arterial pH increased (> 7.45) Serum bicarbonate increased (> 26meq/l) PaCO2 increased PaCO2 rises 7 mmHg per 10 meq/L bicarbonate rise PaCO2 = 0.75 x HCO3 38. The anion gap is frequently elevated to a modest degree [slideshare.net]
There are 3 main causes of bicarbonate increase: Direct administration or production of alkaline-sodium bicarbonate, or other antacids, can lead to metabolic acidosis. Excess bicarbonate is absorbed ad the Co2 levels begin to rise.” [metabolichealing.com]
Treatment
Metabolic alkalosis
The management of metabolic alkalosis consists of targeting the underlying etiology and rehydration with intravenous isotonic saline in chloride-responsive patients. Also, electrolyte replacement is paramount.
Additionally, vomiting should be treated with antiemetics and diuretics may be reduced in dose or discontinued if possible. Specific drugs such as potassium-sparing diuretics, carbonic anhydrase inhibitors, hydrochloric acid (HCl), and others may be of benefit [9]. Also, hemodialysis can be performed in cases of severe alkalosis and volume overload in the context of pre-existing kidney disease [10].
The main approach to the management of this acid-base disorder aims at the treatment of the underlying condition. Also, patients should be encouraged to try breathing techniques to address the hyperventilation. Furthermore, mechanical ventilation settings may need to be adjusted.
Prognosis
The outcomes of metabolic and respiratory alkalosis are influenced by the causes and the contributing comorbidities.
Specifically, an arterial blood pH equivalent to 7.55 is associated with a 45% mortality rate, which dramatically increases to 80% when the pH is above 7.65 [5] [6].
Etiology
Metabolic alkalosis can occur secondary to diuretic use, loss of gastric acid (due to emesis, diarrhea, or nasogastric suction) [1], excessive antacid intake, and other causes.
Respiratory alkalosis develops as a consequence of tachypnea and/or hyperventilation, which may emerge secondary to hypoxia, metabolic acidosis, or stressed states such as with fever. This type of alkalosis arises from both pulmonary and extrapulmonary diseases [2].
Epidemiology
Acid-base disorders are prevalent in hospitalized patients with metabolic alkalosis being the most predominant. Additionally, respiratory alkalosis is the most common in critically ill individuals [3] and in those with high-risk acute heart failure [4].
Pathophysiology
This increase in serum bicarbonate develops in response to 1) loss of acid, 2) consumption of alkali, 3) intracellular shift of hydrogen ions or 4) contraction alkalosis.
Metabolic alkalosis mainly affects the renal and gastrointestinal systems. Once metabolic alkalosis manifests, hypokalemia, a common feature, maintains the alkalosis through various mechanisms.
Alveolar hyperventilation causes PaCO2 to drop below the bicarbonate concentration. In acute episodes or respiratory alkalosis, the pH is basic whereas chronic cases are characterized by a normal or close to normal pH due to metabolic compensation. This condition can affect all organs as it leads to electrolyte and mineral abnormalities.
Prevention
Clinicians caring for hospitalized patients should be aware of how common these acid-base disorders are and take the proper measures to prevent them or manage them early.
Summary
Alkalosis is a condition that is just the opposite of acidosis. It results due to an excess of alkali while acidosis occurs to increased acid level. The imbalance is classified as metabolic and respiratory, which emerges from different causes due to separate processes. The diagnosis is made through assessment of the history, physical exam, and important laboratory tests. Management includes treatment of the underlying disease and the physiological manifestations.
Patient Information
What is alkalosis?
This is a condition in which the blood is alkaline due to the loss of acid or increased amount of bicarbonate. It can also be caused by breathing quickly or deeply. Alkalosis is a very common condition in hospitalized and ill patients.
What are the symptoms?
The symptoms depend on the underlying disease that led to the alkalosis. Patients may experience:
How is it diagnosed?
The doctor will ask questions about the patient's health, perform a physical exam, and order blood tests.
How is it treated?
The treatment depends on the cause of the alkalosis as underlying diseases should be managed. Also, patients will be treated with fluids, electrolytes, and the appropriate medications.
References
- Rimmer JM, Gennari FJ. Metabolic alkalosis. Journal of Intensive Care Medicine. 1987;2:137–50.
- Foster GT, Vaziri ND, Sassoon CS. Respiratory alkalosis. Respiratory Care. 2001;46(4):384-91.
- DuBose TD, Jr. Acidosis and Alkalosis. Kasper DL, Braunwald E, Fauci AS, et al ,eds. Harrison's Principles of Internal Medicine. 16th. New York, NY: McGraw-Hill; 2005. 270-1.
- Park JJ, Choi DJ, Yoon CH, et al. The prognostic value of arterial blood gas analysis in high-risk acute heart failure patients: an analysis of the Korean Heart Failure (KorHF) registry. European Journal of Heart Failure. 2015; 17 (6):601-11.
- Anderson LE, Henrich WL. Alkalemia-associated morbidity and mortality in medical and surgical patients. Southern Medical Journal. 1987; 80(6):729-733.
- Wilson RF, Gibson D, Pereinal MA, et al. Severe alkalosis in critically ill surgical patients. Archives of Surgery. 1972; 105 (2):197-203.
- Phillipson EA, Duffin J. Hypoventilation and Hyperventilation Syndromes. Mason RJ, Broaddus VC, Murray JF, Nadel JA, eds. Murray and Nadel's Textbook of Respiratory Medicine. 4th ed. Philadelphia, PA: Elsevier Saunders; 2005. Vol 2: 2069-70, 2080-84.
- Effros RM, Wesson JA. Acid-Base Balance. Mason RJ, Broaddus VC, Murray JF, Nadel JA, eds. Murray and Nadel's Textbook of Respiratory Medicine. 4th ed. Philadelphia, PA: Elsevier Saunders; 2005. Vol 1: 192-93.
- Gennari FJ. Pathophysiology of metabolic alkalosis: a new classification based on the centrality of stimulated collecting duct ion transport. American Journal of Kidney Diseases. 2011. 58(4):626-36.
- Renaud CJ, Ng WP. Conventional bicarbonate haemodialysis in postgastrectomy metabolic alkalosis. Singapore Medical Journal. 2008;49(5):e121–2.