EMEA Issues Warning on Possible Clopidogrel-PPI Interaction, But Is There Really a Problem?

The European Medicines Agency (EMEA) has now issued a public statement on a possible interaction between clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb) and proton-pump inhibitors (PPIs) and has recommended that the product information for all clopidogrel-containing medicines be amended to discourage concomitant use of PPIs unless absolutely necessary [1].

The UK medicines regulator, the Medicines and Healthcare Products Regulatory Agency (MHRA), has also issued advice to GPs that concomitant use of a PPI with clopidogrel is not recommended unless considered essential, urging a review of the prescribing of PPIs at the next appointment for patients taking clopidogrel.

This follows an "early communication" issued by the US FDA earlier this year, stating that PPIs might interfere with the effectiveness of clopidogrel and that clinicians should reevaluate starting or continuing treatment with a PPI in patients taking clopidogrel.

But several leading cardiologists have voiced concern that the studies on which these warnings are based have many limitations and that it is far from certain whether there really is an interaction between clopidogrel and PPIs.

The EMEA statement points out that, as heartburn and stomach ulcers can occur as side effects of clopidogrel, patients taking clopidogrel often take PPIs to prevent or ease these symptoms. Figures from the UK estimate that around 500 000 patients in that country are currently prescribed clopidogrel and around half are also prescribed PPIs. Many more may be buying omeprazole over the counter, as it is available without prescription. Other PPIs available on prescription include esomeprazole, lansoprazole, pantoprazole, and rabeprazole.

EMEA says the new concern "relates to several recently published studies examining clinical outcomes of clopidogrel users. Taken together, these studies suggest that a significant interaction might occur between clopidogrel and members of the PPI class of medicines, making clopidogrel less effective when given with these medicines." It adds: "One possible explanation for this observation is that some PPIs prevent the conversion of clopidogrel into its biologically active form in the body, reducing the effectiveness of clopidogrel and increasing the risk of heart attack or other conditions involving harmful clotting (eg, strokes). However, as different PPIs have different capacity to affect the metabolism of clopidogrel and as the outcome studies have not fully reflected the different effect of PPIs on activation of clopidogrel, there may be more than one explanation for the effect of this class of medicines on clopidogrel."

Is It Just Confounding?

But some cardiologists contacted by heartwire about this issue are concerned that the clopidogrel-PPI interaction has been given too high a profile, given that the clinical studies suggesting such problems are all observational.

Dr Peter Berger (Geisinger Health, Danville, PA) commented to heartwire : "There are lots of heavily confounded registry data circulating that have been widely reported and given more weight than they deserve."

He noted that these studies have shown that patients on clopidogrel and a PPI do worse than those on clopidogrel alone, but that there are three explanations for why that might be the case:

• PPIs may interfere with the production of the clopidogrel active metabolite.
• PIs may directly cause harm.
• The effect may be due to confounding in the reported studies.

Berger says: "Everyone is assuming that the first explanation--that PPIs interfere with the metabolism of clopidogrel--is the reason, but I believe the third explanation is most likely correct. There is enormous confounding in these studies. Patients taking clopidogrel plus a PPI were much older and sicker than those taking clopidogrel alone. No amount of statistical adjustment can eliminate confounding when there are such large differences. That is always the problem with observational studies."

There are lots of heavily confounded registry data circulating that have been widely reported and given more weight than they deserve.

Berger also points out that there are two randomized databases that are not subject to confounding, and both suggest that there is no interaction between clopidogrel and PPIs. His group has performed an analysis of the CREDO trial, which was presented at the AHA 2008 meeting and showed the same reduction in risk with clopidogrel regardless of whether patients were or were not taking PPIs. And PPI use was independently associated with adverse cardiovascular events at 28 days and one year in the overall population.

The second randomized trial database is the TRITON trial, where, Berger notes, prasugrel showed the same relative benefit over clopidogrel in patients taking a PPI and those not taking a PPI. "Prasugrel is not believed to be affected by a PPI interaction, and if there were an interaction with clopidogrel and PPIs, you would expect to see a larger relative benefit of prasugrel over clopidogrel in patients taking PPIs than those not taking PPIs, but that was not seen," he added.

"In all randomized data so far, patients taking PPIs have more events--that is because they are older, with more comorbidities, and taking more medications. Patients on H2 blockers do worse as well. This tells us that patients who have stomach problems are older and sicker," Berger stated.

He notes that concerns about other drugs that were thought to interact with clopidogrel have been raised before but were subsequently dropped. "This happened with atorvastatin and calcium blockers, but these concerns were refuted in both cases when randomized studies were analyzed," he noted. "While no one knows for sure whether there is an interaction with PPIs or not, I believe that the burden of evidence at the moment supports the view that PPIs do not interact with clopidogrel. I believe the FDA and EMEA statements are premature," he added.

Issue Overpublicized?

Dr Shamir Mehta (McMaster University, Hamilton, ON) is another who believes the evidence for the interaction is shaky. He raised very similar points to Berger's. "The cohort studies suggesting an interaction are very interesting, but they are observational, and patients taking PPIs are fundamentally different from those not taking PPIs. There are probably many unmeasured variables that could account for the difference in events seen. And data from the randomized trials (CREDO and TRITON) do not support an interaction. The fact is that we simply don't know."

Mehta is not critical of the regulatory authorities' statements on the possible interaction, saying, "They are just being cautious." But he expressed surprise about the amount of publicity that this issue has attracted. "There are observational analyses published all the time suggesting different things, but this PPI-clopidogrel interaction has sparked a huge amount of interest. Why this has been singled out I don't know."

There are lots of heavily confounded registry data circulating that have been widely reported and given more weight than they deserve.

The fact is that we simply don't know.

Another to voice a similar view is Dr Gabriel Steg (Centre Hospitalier Bichat-Claude Bernard, Paris, France). He commented to heartwire : "I think the recommendation that clopidogrel and PPIs should not be used together is too strong. Yes, there are good pharmacokinetic data showing an interaction between clopidogrel and omeprazole, but there are other studies suggesting that the clinical impact of the pharmacokinetic interaction may be limited." Steg also points out the hazards of observational studies: "We just need to remember the many observational studies that pointed to the major cardiovascular benefit of HRT in postmenopausal women." He adds: "More important, patients receiving clopidogrel often receive aspirin and other antithrombotics, and the potential for GI bleeds in this population is also real. So it is important to look at the big picture of overall clinical benefit of prevention of GI bleed vis-a-vis the potential for reduced effectiveness. In my view, the data are not definitive yet."

Other experts were more cautious. Dr Shaun Goodman (St Michael's Hospital, Toronto, ON) said: "We’ve been 'fooled' by observational studies before. But there is some biological plausibility based on the genetic-polymorphism data and some platelet-inhibition studies that warrant caution." Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC) pointed out that in some of the observational data sets there was inadequate/incomplete information on concurrent aspirin use and that the higher event rate in the PPI patients may have been simply due to lack of aspirin in patients at risk for GI bleeding. But he added, "Nonetheless, there is a consistency across the observational data that should cause us to take pause."

Is There a Difference Between PPIs?

Another point of uncertainty is whether there may be a difference between individual PPIs, with some pharmacodynamic studies suggesting an interaction with omeprazole but not with pantoprazole. Dr Dirk Sibbing (Deutsches Herzzentrum, Munich, Germany), who conducted one such study, says he believes there is a difference between the various PPIs. "From my point of view, pantoprazole is safe to use with clopidogrel. The clinical evidence, however, is conflicting. But there has been one clinical trial from Canada suggesting an interaction with omeprazole but not with pantoprazole, which fits with our results," he said. He added that from a mechanistic view it is known that omeprazole is metabolized by the CYP219 enzyme, which converts clopidogrel into its active metabolite. And while pantoprazole can also be metabolized by this enzyme, it also uses other routes.

So What Are Doctors Supposed to Do?

All the experts contacted by heartwire agreed that although the data are not definitive, doctors should still be cautious, and PPIs should be prescribed to patients taking clopidogrel only if they are having stomach problems that are not controlled with H2 antagonists. There has been a recommendation that PPIs be given as blanket gastric protection to patients at risk of gastric problems taking dual antiplatelet therapy, but everyone heartwire spoke to said this was no longer advisable, given the possibility of an interaction. Goodman said he didn’t think the data were strong enough to support routine use of a PPI with dual antiplatelet therapy even before this whole interaction issue came to the forefront.

Remember the many observational studies that pointed to the major cardiovascular benefit of HRT in postmenopausal women.

Berger said: "Obviously, given the uncertainty, caution is appropriate, but in patients who we know need a PPI, I would not change or stop therapy at this point just because they are taking clopidogrel."

Sibbing commented: "In our clinic, we try not to use PPIs in patients taking clopidogrel, but if they really need one, we would give pantoprazole." But Berger says he would not differentiate between any of the PPIs or switch a patient off omeprazole and onto a different PPI. "Okay, some pharmacodynamic studies may have suggested a problem with omeprazole but not with the others, but I do not believe it is appropriate to guide therapy based on ex vivo studies of platelet function quite yet," he argued.

Harrington believes that the decision whether to prescribe a PPI to a patient on clopidogrel must be made on an individual patient basis. "A blanket statement to use or not use these drugs in combination seems to be overstepping the available evidence. Caution should be used regarding combining the drugs, selecting types of stents (ie, drug-eluting) that necessitate more prolonged antiplatelet therapies in patients with an increased risk for GI bleeding, etc," he commented. Dr Deepak Bhatt (VA Boston Healthcare System, MA) said: "There is a great deal of confusion. For the time being, it seems reasonable to make sure that patients who are prescribed PPIs really have a good indication for them. Beyond that, it seems premature to change clinical practice, unless new, more compelling data become available."

More Data on the Horizon

All the experts called for a randomized trial to investigate this question. But the only one that was under way--COGENT-1--was stopped prematurely by the sponsor due to financial issues. But other ongoing trials of clopidogrel have been tracking PPI use, including two large studies being reported at the forthcoming European Society of Cardiology meeting--OASIS 7/CURRENT and PLATO--and Berger has also requested permission from Bristol-Myers Squibb/Sanofi-Aventis to analyze the CAPRIE database regarding PPI usage. So more data should be available soon.

References

1. European Medicines Agency. Public statement on possible interaction between clopidogrel and proton-pump inhibitors. May 29, 2009. Available here.

Source : http://www.medscape.com/viewarticle/704651?sssdmh=dm1.488649&src=nldne

The Basic Geriatric Respiratory Examination

The objective of the pulmonary assessment of a geriatric patient is to check for the following:

• Quality of respiratory efficiency;
• Gas exchange; and
• Presence of disease.

Assessing Respiration Efficiency

Of note, if the patient is bedfast, complete evaluation of respiratory efficiency is often less than optimal because chest expansion is not always symmetric and percussion notes may be less resonant.

Respiratory Rate

Although a patient's respiratory rate is often recorded in his or her chart (most often as 20 breaths per minute), cultivate the discipline to obtain it yourself. Count the respirations for a minute and observe the pattern and degree of respiratory effort. Note that moving the diaphragm without moving any air does not count as a breath. Normal respiratory rates for older patients are12 to 18 breaths per minute for those living independently and 16 to 25 breaths per minute for those in long term-care.

Tachypnea. A respiratory rate of 20 breaths per minute (or more than 25 breaths per minute for someone in a nursing home) indicates tachypnea. In such cases, look for the following:

• Infection (especially pneumonia);
• Reactive airways disease (eg, in acute exacerbations of chronic obstructive pulmonary disease [COPD], the patient has air trapping and cannot empty the lungs);
• Congestive heart failure (patient pants in midrespiration);
• Pulmonary embolus (very few elderly patients with pulmonary embolus have respiratory rates less than 16); and
• Metabolic acidosis.

A respiratory rate of more than 30 breaths per minute in a patient with suspected abdominal disease suggests primary chest disease with referred symptoms to the abdomen.

Bradypnea. Bradypnea is a form of hypoventilation, in which the patient has a respiratory rate of less than 10 breaths per minute. In such cases, you might suspect severe myxedema, ingestion of central nervous system (CNS) depressants (eg, narcotics, benzodiazepines), or CNS disease (pontine hemorrhage, hypoglycemia, meningitis).

Respiratory Effort

Normal breathing is quiet and unlabored. If it is labored, it is important to note respiratory effort. In patients with pneumonia or acute abdomen, labored breathing prevents airway closure. Patients who have air hunger will often breathe with an open mouth. Pursed lip breathing mainly in expiration is seen in end-stage emphysema and suggests small-airway disease with terminal bronchiole collapse. Expiring with pursed lips increases the end-expiratory pressure, keeping the airways open and reducing the work of breathing. (It takes more work to put the first breath into a balloon than to add a breath to an already half-filled balloon.)

Audible Breath Sounds

Pay attention to the breath sounds. Wheezing, a musical sound, is an important clue to reactive airways or local obstruction. Coughing indicates lower airway irritation. Stridor (a high-pitched shrieking sound) implies partial airway obstruction. Expiratory stridor without inspiratory stridor suggests lower airway obstruction. Stridor on inspiration and expiration implies airway obstruction at the glottis. Of note, inspiratory stridor suggests obstruction in the oral airway or epiglottis and is a medical emergency.

Respiratory Patterns

Check for respiratory patterns and signs that indicate specific conditions. For example, inspiration interrupted by cough suggests pleuritic pain or inflammation. The following are other patterns and signs to look for.

Kussmaul's Respiration. Kussmaul's respiration is deep rapid respiration (an exaggeration of normal) in metabolic acidosis and is classically associated with diabetic ketoacidosis. Patients with Kussmaul's respiration may have an increase in tidal volume. While talking, they need to breathe between phrases, so their speech pattern can seem choppy.

Cheyne-Stokes Respiration. The pattern of Cheyne-Stokes respiration is one of increasingly deep respirations followed by a steady diminution of breathing until an apneic episode occurs, which can signify prolonged circulatory time or primary neurologic disease. Among the differential diagnoses are the following:

• Primary CNS disease;
• Chronic heart failure, meningitis;
• Pneumonia;
• Carbon monoxide poisoning; and
• Medications (eg, morphine).

Obesity may be present. Some patients will show pupillary dilation with rapid breathing and pupillary contraction with apnea.

Biot's Breathing. Biot's breathing is characterized by irregular breathing (the "atrial fibrillation" of respiration) with sudden apneas. It suggests CNS disease and can be a sign of increased intracranial pressure or meningitis.

Apneustic Breathing. Apneustic breathing is seen in severely ill patients with coma. The patient holds his or her breath at the end of inspiration until the Hering-Breuer (carotid body) reflex initiates exhalation. This breathing pattern suggests pontine disease.

Chest Movement During Respiration

The next part of the chest inspection is to observe the patient's chest movement during respiration.

Use of Accessory Muscles

Using accessory muscles implies that the forced expiratory volume in 1 second (FEV1) is decreased to 30% of normal, which is usually between 1.0 and 1.5 liters per second. In such cases, a sitting patient may lean forward with hands propped on the knees. Sternocleidomastoid tension is often present, which is indicated by tense neck muscles, with the muscle being thicker than the patient's thumb.

Diaphragm Movement

Diaphragm movement can sometimes be seen with inspiration as a flickering along the lateral chest. A loss of this movement on one side indicates a paralyzed hemidiaphragm (Litten's sign). Diaphragmatic movement is usually not visible in overweight people.

Chest Symmetry

To check chest symmetry, observe the sides of the chest from the patient's back. Symmetric but decreased expansion suggests extreme old age or emphysema. Decreased chest expansion resulting from substernal goiter is Bryson's sign. Symmetric but increased expansion suggests paralysis of the diaphragm with compensatory intercostal contractions. Asymmetric expansion suggests pneumonia, a large pleural effusion, rib fracture, or pneumothorax. With hemiplegia, the affected side moves more than the unaffected side during quiet respiration but becomes more sluggish with forced respiration (Jackson's breathing sign).

Paradoxic Chest Movements

Paradoxic sternal movement suggests trauma or multiple rib fractures. Paradoxical abdominal movement, in which the abdomen moves out with expiration, can be a sign of a paralyzed diaphragm, respiratory failure, or fatigue during an exacerbation of COPD. Intermittent paradoxic abdominal movement may be caused by muscle fatigue from respiratory pump failure (respiratory alternans). Epigastric depression with inspiration suggests large pericardial effusion or a paralyzed diaphragm (Duchenne's sign).

Intercostal Retractions

Intercostal retractions suggest an imbalance between the negative pressure generated and the ability of the lung to expand. Generalized retractions are a sign of significant inspiratory obstruction. Focal retractions suggests bronchial obstruction, flail chest, or constrictive pericarditis (Broadbent's sign) if over the heart. With flail chest, the ribs themselves show paradoxic movement. Unilateral loss of normal retractions suggests pleural effusion, pneumothorax, or consolidation.

Bulging Interspaces and Apices

Bulging interspaces on inspiration suggests a tension pneumothorax, a large pleural effusion, emphysema, or reactive airways disease. Elevation of the supraclavicular space in an asynchronous manner suggests pleural effusion as the lung floats like a cork on the pleural fluid. The side with the fluid will elevate first.

The Costal Angle (Hoover's sign)

An especially useful observation is to watch the costal angle during respiration (Hoover's sign). Normally this angle should increase as the intercostal muscles open the chest as the diaphragm contracts. Hoover's sign is paradoxic closing of the costal angle with inspiration because of the loss of intercostal contribution secondary to air trapping. This sign indicates chronic obstruction and an FEV1 less than 1 liter per second. Restrictive lung disease by itself does not produce Hoover's sign.

Unilateral Movements

If there are unilateral movements, consider the source of the inequality. One side moving more laterally implies significant atelectasis if it is pulling up from above or subphrenic abscess if pushing up from below.

If one side moves more medially than the other, consider intercostal paralysis, pleural effusion, or tension pneumothorax. Unilateral narrowing of the intercostal spaces suggests pneumothorax or inflammation (Przewalski's sign). If you see decreased medial movement with normal lateral movement, consider cardiac enlargement, severe right heart failure, and pericardial effusion.

Palpation

Palpate the Lateral Chest Walls

Palpation over the lateral chest wall can provide helpful information on respiratory excursion. Make sure your hands are warm before beginning. Feeling an area of localized warmth in a febrile patient could represent an empyema. Appreciating a mass in the chest wall could represent a rib fracture (there may be an area of point tenderness and possibly ecchymosis), tuberculosis, nocardia, or actinomycosis. A mass felt in an interspace suggests abscess (possibly actinomycosis, tuberculosis, or empyema necessitans) or lymphadenopathy from lymphoma. Detecting crepitus suggests subcutaneous emphysema from a rib fracture, ruptured bleb with pneumothorax, esophageal rupture, or abdominal perforated viscus with retroperitoneal air tracking.

Palpate the Trachea

If you have not already done so, palpate the trachea. Check the lateral tracheal wall with the clavicular heads to determine whether it is midline. Deviation from the midline is significant.

Palpate Rib Expansion

Palpate the rib expansion segmentally. For examining the upper lobes, place your hands on each upper lobe with the thumbs under each clavicular head. Watch for symmetric thumb expansion with each inspiration. To check the middle and lingular segments, place your hands across the lower chest with each thumb at the fifth intercostal space on the sternum. Watch for symmetric thumb expansion with each inspiration. A lack of symmetric movement suggests bronchial stenosis on the side with the reduced movement.

To evaluate the lower lobes, place your hands across the lower chest anteriorly, with each thumb at the costal margin.

It is especially useful to check the costal angle during respiration. Normally the angle increases on inspiration as the intercostal muscles open the chest and the diaphragm contracts. Paradoxic movement with a decrease in the costal angle on inspiration that is caused by severe air trapping in COPD (FEV1 <>

Tactile Fremitus

Checking for tactile fremitus requires detecting palpable vibrations. Have the patient say "toy coin" each time you touch the chest with the ulnar side of your hand. The "oy" sound is the key to producing the vibration. (It is sometimes recommended to ask the patient to say "99." However, the origin of this came from the German words for "99," which in that language contains "oy" sounds.). Feeling increased vibration (fremitus) over an area of dullness to percussion suggests consolidation or direct communication between the bronchus and the chest wall. Appreciating decreased fremitus over an area of dullness suggests pleural effusion or pneumonectomy. Use both hands to compare each side simultaneously. Begin at the apices posteriorly and work down the back, then go anteriorly to the apices. Normally the right apex will have slightly more fremitus than the left because of the aortic position. Note the level of the diaphragm.

Pain on Palpation

Localized pain on palpation suggests early herpes zoster, rib fracture, or costochondritis (Tietze's syndrome). Sternal tenderness can be a sign of fracture, leukemia (classically the lower third of the sternum), other blood marrow abnormalities, metastatic prostate cancer, or xiphoidalgia. Pneumonia can produce tenderness and spasm of the insertion of the sternocleidomastoid muscle.

Percussion

General Points

As with palpation, make sure your hands are warm before you begin percussion. Start at the back and check each side to compare the quality of the sensation. It is key to keep the wrist loose and the hand floppy. As you percuss, consider the characteristic of the structure you are percussing. One trick is to practice over a table percussing from the center toward the legs. Notice how the percussion note feels firm when over the leg of the table. Close your eyes and practice until you can reliably stop over the leg. Sometimes an elderly patient is too ill to sit up and percussion must be accomplished with the patient in the lateral decubitus position. This position can add some artifacts of lung compression, producing dullness in the mid lung fields of both the dependent and upward lungs. Of note, the feel of the resonance may be more sensitive than the sound of the percussion note, especially in a noisy setting such as a crowded emergency room, where subtleties of sound are more difficult to appreciate.

Basic Percussion Techniques

There are 3 basic percussion techniques: the light pat (an excellent general technique for pulmonary examination), the direct percussion, and the indirect percussion (what students are generally taught as percussion).

1. Light pat. Gently pat the back on each side starting at the apices and moving down to the diaphragm.
2. Direct percussion. Place your dominant hand on the skin and raise your forefinger and tap on the skin directly.
3. Indirect percussion Place your non-dominant hand on the skin and with your dominant middle finger tap the middle finger of your nondominant hand at the sistal interphalangeal joint.

Some experts believe that the second and third techniques are best used to define an interface such the cardiac border or the upper border of the liver.

The Sequence of Percussion

The patient should be upright if at all possible. Percuss down the posterior midclavicular line on each side of the chest. Note the diaphragmatic excursion by checking its level during expiration and then during deep inspiration. Normally this excursion is about 4 centimeters. Compare each side.

After percussing the diaphragm, percuss down the midaxillary line on each side. An elevated left hemidiaphragm is clearly abnormal and implies volume loss, paralysis of the left hemidiaphragm, or a left upper quadrant abdominal mass. An elevated right hemidiaphragm is normal but can suggest volume loss, a right upper quadrant mass, and a paralyzed right hemidiaphragm.

Next, percuss across the trapezius from the shoulder to the base of the neck to check Krönig's isthmus (of resonance) on each side. This area is significantly more resonant than the shoulder or the base of the neck. Loss of normal resonance in this area suggests upper lobe disease.

Percuss the clavicles. Dullness on one side suggests upper lobe disease.

Finally, percuss over the right middle lobe in the right midchest and along the left anterior chest.

Dullness and Its Indications

Dullness to percussion implies consolidation, pleural fluid, or pleural scarring. Parenchymal consolidation suggests pneumonia or cancer. If you suspect pleural fluid, recheck your percussion with the patient in the lateral decubitus position with the dull side up. Look for any change in dullness caused by fluid shift. No change in dullness with a change in position implies either consolidation or loculated fluid. Dullness to percussion plus absent breath sounds caused by hydatid disease in the lungs is Bird's sign.

Dullness in the medial base of the lung (Grocco's triangle) near the spinous process is contralateral to a pleural effusion (or significant pneumonia) and is ipsilateral to a massive pleural effusion or pericardial effusion (obviously on the left side).

Dullness below the left scapula (Ewart's sign) or below the right scapula (Conner's sign) suggests a large pericardial effusion.

Pleural effusion may be suggested by the following:

• Increased rib vibration in the anterior chest to percussion posteriorly (Kellock's sign);
• Change in the percussible dullness with change in position (D'Amato's sign); or
• Hyperresonance just above an area of dullness (skodaic hyper-resonance).

With small pleural effusion, dullness is in the T9 to T11 interspaces. In pneumothorax, the percussion note is more resonate (Biermer's sign). In this case, check for hyperresonance over the midclavicle. Confirm by appreciating decreased breath sounds over the hyperresonant side and with the coin test (see below).

Noting a band of hyperresonance near the diaphragm suggests subphrenic abscess or lower lobe pneumonia.

Auscultation

General Points

Make sure that the listening area is quiet, and importantly, do not listen through the patient's clothing. Warm your stethoscope either by carrying it in your pants pocket or by vigorously rubbing it. One strategy is to place a rubber membrane on the bell and have the patient breath deeply with the mouth open. Make sure that your stethoscope bell is securely placed flat on the chest and that you are not breathing on your tubing. In fact, breathe on the tubing beforehand to appreciate the low-pitched rustling sound your breath produces. Be sure that your earpieces are securely in your ears to exclude environmental noise.

Listen to at least 2 respiratory cycles at each location. All breath sounds should increase in pitch with inspiration and decrease with expiration. If patient has been intubated, listen for bilateral breath sounds and over the epigastric area to help determine the tube placement.

Begin at the bases and work up the back. Starting at the bases allows you to appreciate any basilar crackles secondary to atelectasis or early congestive heart failure. If you start at the apices and work down, such crackles might disappear by the time you get to the bases. If you hear additional noises make sure they are coming from the patient's chest and not from the skin, muscles, or other extraneous source. For example, body hair can produce a crackling sound that resembles dry cellophane crackles.

Quality of Breath Sounds

Alveolar (vesicular) breath sounds are normal but pathologic processes cause these sounds to disappear. Upper airway or bronchial (tubular) breath sounds are normal over an airway but hearing these sounds in the peripheral lung fields suggests consolidation or lymphadenopathy. They also may be heard at the top of a pleural effusion. Bronchial breath sounds are only heard at the top of the effusion. Pay attention to the inspiratory to expiratory ratio of breath sounds. Chronic obstructive lung disease increases the expiratory phase of respiration. Hearing equal inspiratory and expiratory sounds suggests respiratory obstruction (Grancher's sign). Localized prolongation of expiratory sounds is Jackson's sign, which can sometimes signify a localized obstruction such as an endobronchial mass.

Loudness of Breath Sounds

Increased breath sounds over an area of dullness suggests consolidation. If there is upper lobe consolidation, consider tuberculosis, Pancoast's tumor, or aspiration pneumonia. Signs of middle lobe consolidation suggest pneumonia, malignancy, or conditions producing lymphadenopathy (middle lobe syndrome). Lower lobe consolidation suggests pneumonia, aspiration, or pulmonary infarct. Decreased breath sounds over an area of consolidation suggest pleural effusion or pneumonectomy.

Adventitious Breath Sounds

If there is stridor (see above), listen over the trachea or at the base of the neck to see if loudness is greatest there. Stridor heard on inspiration is a red flag for a medical emergency and you should consider epiglottic obstruction, epiglottitis, vocal cord dysfunction, tracheal obstruction, whooping cough, neoplasm, foreign body, tracheal stenosis, or palatal obstruction. Stridor only in expiration suggests lower airway obstruction, such as from a foreign body.

Wheezes

Wheezes are musical sounds that indicate airway obstruction, which when it occurs during expiration, suggests a source within the chest. Wheezing that occurs on inspiration suggests obstruction in the trachea (outside the chest). Hearing both inspiratory and expiratory wheezes is more concerning than hearing either alone. Focal wheezes help to localize the site of obstruction. End-expiratory wheezes suggest reactive airways (asthma) and imply bronchiolar disease. Peak flow is reduced significantly. Hearing wheezes throughout expiration suggests asynchrony of one lung area with another, such as occurs with organophosphate poisoning. Hearing end-inspiratory wheezes implies a small airway opening in the deflated section of lung. This finding suggests chronic bronchitis, bronchiectasis, or organophosphate poisoning. Hearing wheezes throughout inspiration implies a fixed stenosis or obstruction of the upper tracheal bronchial tree, such as in interstitial fibrosis or hypersensitivity pneumonitis.

Crackles (Rales)

Inspiratory crackles are common in elderly people. Early inspiratory crackles, however, imply significantly decreased FEV1/forced vital capacity caused by broncho-obstructive disease as a result of chronic bronchitis, emphysema, or reactive airways disease. Midinspiratory crackles suggest bronchiectasis, whereas late inspiratory crackles suggest restrictive (alveolar) disease caused by congestive heart failure, idiopathic pulmonary fibrosis, sarcoidosis, or drug toxicity.

Localized midexpiratory crackles can be a sign of bronchiectasis or pneumonia. Note the location of expiratory crackles. If their location changes with the patient's position, consider congestive heart failure because this implies an increased pulmonary capillary wedge pressure (above 25 mm Hg). Fixed crackles suggest fibrosis or pneumonia.

Note the quality of the crackles. Peripheral lesions tend to increase the pitch (fineness) of the crackles. Fine crackles (like crackling cellophane) suggest interstitial fibrosis, sarcoidosis, or asbestosis. Coarse Velcro®-like crackles suggest chronic pulmonary fibrosis. Moist crackles (resembling the sound of the fizz of a carbonated drink) suggest congestive heart failure. Posttussive rales (crackles) suggest parenchymal disease or lung abscess.

Rhonchi

Rhonchi are coarse flapping sounds that suggest fluid or mucus in an airway.

Amphoric Breathing

Amphoric breathing is a low-pitched sound resembling blowing over a soft drink bottle (an amphora). To appreciate the nature of this sound, trying listening over the occiput while the patient whispers "wahoo." Amphoric breathing is never heard in the presence of alveoli so hearing it suggests alveolar destruction with air going into and out of a cavity and signifies a large bullae or lung abscess. Disappearance of amphoric breathing suggests that something has occupied the void (aspergillus fungus ball or fluid).

Pleural Friction Rubs

Pleural friction rubs are leathery, creaky sounds similar to the sound of slowly rubbing your palms together. They do not have a musical quality, like a wheeze does, but suggest 2 inflamed pleural surfaces (the parietal and visceral pleura) rubbing together. They can occur on both inspiration and expiration, but they usually occur with inspiration and tend to be localized. Hearing a pleural friction rub implies neoplasm, pulmonary infarction, pneumonia, tuberculosis, or systemic lupus erythematosus. A sternal friction rub heard when the patient raises and lowers the arms suggests aortic arch aneurysm or fibrotic mediastinal tumor (Perez's sign).

Special Sounds and Signs

d'Espine's Sign. During auscultation, when you reach the level of the midscapula (about T5), check for an important sign of a posterior mediastinal mass (d'Espine's sign). Listen on either side of the vertebral column and compare the quality and intensity of these sounds with those over the spinous process. Normally, the lateral sounds are louder and more distinct. With a positive d'Espine's sign, the vertebral breath sounds are loud and upper airway sounds are of greater intensity than the corresponding lateral lung sounds. This implies continuity between the main stem bronchus and the vertebrae and suggests malignancy, lymphoma, metastatic cancer, tuberculosis, sarcoidosis, and other causes of mediastinal lymphadenopathy. Listen for egophony, bronchophony, and whisper pectoriloquy. These may be more sensitive for posterior mediastinal lymphadenopathy than the change in breath sounds. If d'Espine's sign is present, try also percussing over the spinous processes of T1-T5. The appearance of red spots over the spinous processes of T1-T5 after percussing them suggests bronchial lymphadenopathy (Cattaneo's sign). False positives of d'Espine's sign can occur in severe kyphosis, which should be obvious.

Egophony (Goat Sound). Egophony (or goat sound) is an "e" to "a" change and is considered the most sensitive sign of pulmonary consolidation. Have the patient say "e." A compressed lung will produce a bleat like a goat, changing the "e" to an "a" sound. For practice, listen over the skull or the base of the neck where this "e" to "a" change is normal. Egophony may be present along the top of a pleural effusion. It may also be present over a massive pleural effusion caused by significant lung compression. Extensive pulmonary fibrosis can also produce egophony.

Whisper Pectoriloquy. Whisper pectoriloquy is the second best sign of consolidation. Have patient whisper "66 whiskeys please," which produces hissing sibilant "s" sounds. When bronchial breathing is abnormal, the sounds will be more distinct and you can more easily appreciate the words whispered.

Bronchophony. In bronchophony, spoken sounds seem more distinct when listening over a consolidated or compressed lung. Have the patient say a sentence like "UNC is number one," or repeat a word such as "99" several times. With consolidation or compressed lung, the words will be heard clearly over the involved area.

Expiratory Time. Have the patient take a deep breath and exhale as quickly as possible. Listen over the trachea. Hearing expiratory sounds for more than 6 seconds suggests airway obstruction Another but less accurate method is to listen over the upper posterior chest and use a 3-second threshold.

The Test for Pneumothorax. For this test, the patient must be sitting upright and asked to hold a large silver dollar, flat against the chest just below the midclavicle. Tap the silver dollar with another coin. (Note: A Susan B. Anthony dollar or coins such as quarters or nickels are too small and will not work. It must be a pre-1964 silver dollar.) A pneumothorax or a large bulla will produce a loud ringing bell-like sound rather than the usual metallic tap. Tuning forks can sometimes be used as an alternative.

Shephard's Sign of Sleep Apnea. In some patients with sleep apnea, a sonorous expiratory wheeze will develop at the base of the neck. Listen with the patient supine and breathing through his or her nose.

Identifying Specific Conditions

Differentiating Pleural Effusion From Consolidation

Because both pleural effusion and consolidation produce dullness, percuss just above the dullness, preferably using the light pat technique. The following clues each indicate that the presence of a pleural effusion is more likely:

• Increased rib vibration in the anterior chest to percussion posteriorly (Kellock's sign);
• Change in the percussible dullness with change in position (D'Amato's sign);
• A rim of hyperresonance heard just above the dullness (skodaic hyperresonance);
• Increased resonance of the thoracic spinous processes (Korányi's sign);
• An "s"-shaped line of dullness on percussion of the chest (Damoiseau-Ellis line); and
• Change in the tympanitic note above a pleural effusion when the patient opens and closes his or her mouth.

The following are additional techniques for differentiating between pleural effusion and consolidation:

• Listen to the quality of breath sounds in the area of dullness. Hearing an increased intensity of sounds suggests consolidation; a decreased intensity suggests pleural effusion;
• Listen for egophony (see discussion above). A change to a goat-like "a" sound after saying "e" in the area of dullness suggests consolidation (Shibley's sign). Egophony -- either "e" to "a" or "u" to "a" (Karplus' sign) -- just above an area of dullness suggests pleural effusion;
• Hearing no sound at all over an area of dullness implies resection; and
• Listen for whisper pectoriloquy by having the patient whisper "66 whiskeys please." Clearly hearing the phrase in an area of dullness suggests consolidation; hearing no sound suggests pleural effusion.

If the signs suggest pleural effusion, gently move the patient while listening over the effusion. Hearing a sloshing sound suggests hydropneumothorax. Note the location of the effusion. A right-sided pleural effusion suggests congestive heart failure. A left-sided effusion suggests pancreatitis, pulmonary infarct, pericarditis, ascites, or a ruptured thoracic duct.

Signs of Cavitary Lung Disease

Pulmonary cavities may be identified in several ways. In patients with pulmonary cavities, the percussion note may change when the patient opens and closes his or her mouth (Wintrich's sign). While listening over a pulmonary cavity, harsh inspiratory sounds that quickly diminish in intensity (Seitz's sign) may be heard. Forced inspiration can lower the pitch of the sound over a cavity (Friedreich's lung sign). Cough following apical percussion producing an area of apical tympany suggests cavitary disease (Ernis' sign).

Signs of Pleural Inflammation

Decreased rib expansion can be caused by an inflammatory process in the lungs (Bethea's sign). Palpable intercostal muscle rigidity suggests pleural inflammation (Pottenger's sign); disappearance of this sign can indicate empyema (Ramond's sign).

Pain offers a clue to possible pleuritic inflammation. With pleuritic inflammation, the patient will lie with the good side down (Andral's decubitus sign). Pleural inflammation can produce sensitivity of the upper back and shoulder muscles to palpation (Sternberg's sign). Pain from pleural irritation may also be referred to the shoulder (Capp's sign). Pain on palpation on the left upper abdominal quadrant (the mirror image of Murphy's point) suggests lower lung pleural inflammation (de Mussey's sign). Chest pain that increases with bending toward the pain suggests intercostal neuralgia; increase in pain bending away from the pain suggests pleuritic pain (Schepelmann's sign).

Examining the Patient With Respiratory Distress

Demeanor and Posture

Patients in respiratory distress may appear restless, agitated, or drowsy. The patient's eyes may be prominent. Patients in respiratory distress will often sit leaning forward using their accessory muscles. Hypertrophy of the sternocleidomastoid may be present and the patient may have calluses on the extensor surface of the forearm or distal thigh (Dahl's sign) as evidence of the chronicity of their lung disease. Patients who sit leaning forward with their legs dependent (Fowler's position) may have severe heart failure. Patients leaning forward with their head protruding forward as if sniffing flowers may have epiglottitis.

Breathing difficulty when sitting up and relieved when supine is platypnea and implies severe upper lobe disease. Patients lying on one side (lateral decubitus position) tend to place the good lung in the dependent position to maximize ventilation-perfusion matching. However, if a pleural effusion is present, it will tend to be on the dependent side.

Skin Color

Obviously the patient's skin color gives important clues to the level of oxygen saturation. Cyanosis suggests at least 5 grams of deoxyhemoglobin. If only the nail beds are cyanotic, the peripheral circulation is clamped down or slowed.

Clubbing of the Fingernails and Schamroth's Sign

One way to see whether the fingers are clubbed is check for Schamroth's sign. Have the patient place both forefinger nails together. If you can see a small diamond space between the nails, the nails are not clubbed. If the diamond is not visible, Schamroth's sign is positive and clubbing is present. Pulmonary causes of clubbing (not an exhaustive list) include the following:

• Bronchogenic carcinoma;
• Alveolar cell carcinoma;
• Pulmonic abscess;
• Interstitial pulmonary fibrosis;
• Sarcoidosis;
• Beryllium poisoning; and
• Pulmonary arteriovenous fistula.

Some cardiac and gastrointestinal disorders can also cause clubbing.

Chest Shape and Symmetry

Chest wall deformities can have a significant impact on respiratory dynamics. For example, scoliosis and kyphosis are common in elderly people. The following conditions should also be looked for.

A barrel-shaped chest, indicated by increased anterior-posterior diameter, suggests air trapping caused by chronic lung disease. In some cases of emphysema, the AP diameter may not really be increased but is an optical illusion because of decreased abdominal diameter. Emphysema is also suggested in patients with a thin wiry habitus and distended arm veins.

Pectus excavatum (funnel chest) occurs when the sternum is depressed, creating a funnel-like shape. It is associated with Marfan's syndrome and congenital abnormalities in the respiratory tract and heart.

In pectus carinatum (pigeon chest), the sternum sticks out like a ridge on the chest. It is associated with acromegaly, Marfan's syndrome, and congenital problems of the diaphragm.

Tracheal Location

Normally the trachea is slightly to the right of the midline. Atelectasis and consolidation shifts the trachea toward the involved side. Pleural scarring will cause the trachea to deviate to the involved side during inspiration. Pneumothorax will pull the trachea to the opposite side, whereas massive pleural effusion or goiter will push the trachea to the opposite side

Venous Patterns

Note the venous pattern over the chest, which may indicate specific conditions. Unilateral venous distension suggests an underlying pulmonary neoplasm. Juicy collaterals can be seen in superior vena cava syndrome. Varicosities over the C7-T3 spinous processes is Lombardi's sign of tuberculosis. Fine telangiectasias along the border of the costal margin are commonly seen in elderly men.

Reading List

Maitre B, Similowski T, Derenne J-P. Physical examination of the adult patient with respiratory diseases: inspection and palpation. Eur Respir J. 1995;8:1584-1593. Available at: http://www.erj.ersjournals.com/cgi/reprint/8/9/1584.pdf Accessed May 21, 2009.

Bureau of Medicine and Surgery, Department of the Navy. Hospital Corpsman Sickcall Screener's Handbook. Thorax, Lungs, and Respiratory Disorders. BUMEDINST 6550:9A; 1999. Available at: http://www.brooksidepress.org/Products/OperationalMedicine/DATA/operationalmed/Manuals/
CorpsmanSickcall/ThoraxLungsResp.html Accessed May 21, 2009.

Source : http://cme.medscape.com/viewarticle/703696

Some Surprises in Update to European Hypertension Guidelines?

The European Society of Hypertension (ESH) is set to stir up the field of BP guidelines later this year, when it publishes an update to its 2007 recommendations. During a special session at the European Meeting on Hypertension 2009 here yesterday, Dr Giuseppe Mancia (University of Milan Bicocca, Monza, Italy), outlined the main changes and said the complete new guidelines will be published in the October 2009 issue of the Journal of Hypertension.

Key among the changes will be the recommendation of a lower threshold level--around 120 mm Hg systolic and 70 mm Hg diastolic--below which it could be dangerous to reduce blood pressure in high-risk individuals, representing the so-called J-curve phenomenon, Mancia said. And rather than emphasizing which antihypertensives should be used first-line, second-line, etc, the new guidelines will instead advise tailoring therapy to individual patient circumstances, he explained.

Also new will be the first European guidelines on the management of high blood pressure in children and adolescents, which will be published in the September 2009 issue of the Journal of Hypertension, Dr Empar Lurbe (University of Valencia, Spain) told meeting attendees. Of key importance among these recommendations will be the indications for future research, she said. "Currently, in Europe, we don't have reference data on adolescents and children, we have to rely on data from the US," so it's imperative that baseline values based on the European pediatric population are established. Other important future endeavors include the development of accurate nonmercury sphygmomanometers for pediatric use and drug trials in this "therapeutic orphan" patient population, she said.

Doctors are also eagerly awaiting new American guidelines on hypertension--the eighth edition of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) is expected later this year--but many are unsure exactly what to expect.

J-Curve: A Narrow Window of Optimum BP for High-Risk Individuals

Mancia told the meeting that the decision to update the 2007 European hypertension guidelines was taken "because, since then, there have been a number of trials published that could change the recommendations, or in other instances, new data have reinforced the recommendations made."

There are also other situations where "difficult and controversial conclusions" have created confusion, he explained, adding that although the new guidelines document "is still under refinement, the committee agrees on the principles and the issues, which is why I can present it today."

In terms of hypertension treatment thresholds and goals, these will remain pretty much the same as in 2007, he said, with a treatment threshold of 140/90 mm Hg or greater for general hypertension, and a therapy goal of <140/90 mm Hg for this population. For high-risk individuals, the treatment threshold is 130/85 or greater and the treatment goal should be <130/80 mm Hg, although he acknowledged that "the more aggressive goal in high-risk individuals is not supported by outcomes trials, so further hard evidence is needed."

But with the decision to include a lower threshold below which BP should not be lowered in high-risk individuals, this means the window of optimum BP will be narrow in high-risk individuals.

Explaining the new decision, Mancia said: "In 2007, apart from HOT, all the trials were retrospective, but we knew there must be a BP below which perfusion of vital organs is compromised. Now, a number of studies--including INVEST, ONTARGET, VALUE and TNT--have been remarkably consistent" in showing that there is indeed a floor for high-risk individuals below which BP should not be lowered "in order to avoid harm," he noted. "If BP approaches 120/70 in high-risk individuals, a J-curve appears, and this should generate concern," he said.

Treat the Elderly; Tailor Treatment to Specific Patients

Another important change since 2007 will be the recommendation for the very elderly, those aged over 80, in whom the benefits of lowering blood pressure had previously been "inconclusive," Mancia explained.

"Now things have changed with the HYVET data, which showed major benefit, suggesting that we prolong the life of these very old people if we control their BP when BP is elevated," although the trial does have some limitations, he commented.

In terms of choice of drug therapy for hypertension, in 2007 there were five drug classes listed as suitable for initiation of therapy--diuretics, ACE inhibitors, calcium-channel blockers (CCBs), angiotensin receptor blockers (ARBs), and beta blockers.

"Since then, a number of important trials have added new evidence in favor of the protective effects of ACE inhibitors, ARBs, and CCBs and have reinforced the position of these drugs as options to treat hypertension and other conditions such as heart failure and renal disease."

One of the controversies with regard to drug choice has been the debate about the use of beta blockers, he said, with the UK NICE and the British Society of Hypertension removing them from first-, second-, and even third-line choice of treatment in 2006.

"In 2007, the [ESH] committee felt this was not an appropriate decision, as beta blockers were usually employed together with diuretics in virtually all trials, so it was difficult to discriminate what was the favorable or unfavorable role of one drug class or another," he noted. And although there have been negative trials with beta blockers--LIFE and ASCOT--there have also been positive ones, such as HAPPHY, IPPPSH, STOP, INVEST, and UKPDS, he noted.

The totality of evidence now shows different conclusions for different patient populations, he said. "For example, for stroke prevention, beta blockers are inferior to calcium antagonists, but for congestive heart failure prevention, beta blockers are superior to calcium antagonists and similar to other drugs," he noted.

In fact, reducing the emphasis on the step-by-step approach to treatment in general--not recommending particular antihypertensives as first-line, second-line therapy--is another central tenet of the new guidelines, Mancia noted.

"Classifying agents as first choice, second choice, third choice, etc, betrays reference to an average patient who hardly exists in clinical practice," he said, adding: "It is much better to indicate which drug might be preferred in which patient under which circumstance. All drugs have advantages and disadvantages, and we have to try to see in which conditions the advantages of a drug come out."

But Combination Therapy Remains Choice for High-Risk Individuals

But the new guidance will again stress the importance of using combination therapy first-line in high-risk individuals, as advised in 2007, he said, although new data in the intervening two years are helping to refine these recommendations, he noted.

"In 2007, we took a strong stance in favor of combination treatment. This has been shown again--trials such as ACCOMPLISH, ADVANCE, HYVET, ASCOT and ONTARGET are changing the picture. We have to lower BP rather quickly [in these patients] to try to prevent a catastrophe," and more recently, studies have shown there is less discontinuation of treatment in this patient population if treatment is started with combination therapy, Mancia said.

"The evidence is now in favor of giving such patients a blocker of the renin-angiotensin system (RAS)--such as an ACE inhibitor or ARB--with a calcium-channel blocker or diuretic." However, he stressed: "This does not mean that other combinations cannot be used or are not useful."

Another issue that was debated was whether the use of an ACE-inhibitor/ARB combination "should be banned," on the basis of the ONTARGET findings, he noted. But he indicated this would likely not be the case, "because this remains an effective treatment to lower proteinuria compared with single blockade of the RAS system, and this is regarded by nephrologists to be important whenever proteinuria is not reduced sufficiently by one agent.

"But, of course, the data from ONTARGET cannot be forgotten," he stressed, "which means dose titration must be cautious, with frequent monitoring of renal function and BP and close attention to environmental circumstances that might reduce bodily fluids."

Source : http://www.medscape.com/viewarticle/704457?src=mpnews&spon=34&uac=133298AG

Malaria

Introduction

Background

Malaria is the most deadly vector-borne disease in the world. Although typically an illness of tropical regions of the world, more than 1500 cases (nearly all foreign-originating) are diagnosed in the US each year. In some parts of the world, malaria is known as paludism (paludismo). Blackwater fever refers to the dark urine sometimes seen as a result of severe red blood cell hemolysis from malaria.

At least 10 of the more than 200 parasitic protozoa species of the genus Plasmodium (Plasmodium ovale, Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum), and Plasmodium knowlesi, cause human malaria. P falciparum causes the most severe morbidity and mortality.

Malaria is primarily transmitted through the bite of an infected female Anopheles species mosquito. Malaria also can be transmitted via a blood transfusion or congenitally between mother and fetus, although these forms of infection are rare.

At risk for contraction of malaria are persons living in or traveling to areas of Central America, South America, Hispaniola, sub-Saharan Africa, the Indian subcontinent, Southeast Asia, the Middle East, and Oceania. Of these areas, sub-Saharan Africa has the highest occurrence of P falciparum transmission to travelers from the United States.

Pathophysiology

The vector, the Anopheles species mosquito, passes plasmodia, which are contained in its saliva, into its host while obtaining a blood meal. Plasmodia enter circulating erythrocytes (RBCs) and feed on the hemoglobin and other proteins within the cells. One brood of parasites becomes dominant and is responsible for the synchronous nature of the clinical symptoms of malaria. Malaria-carrying female Anopheles species mosquitoes tend to bite only between dusk and dawn.

Schema of the life cycle of malaria. Image courtesy of the Centers for Disease Control and Prevention.

This protozoan brood replicates inside the cell and induces RBC cytolysis, causing the release of toxic metabolic byproducts into the bloodstream that the host experiences as flulike symptoms. These symptoms include chills, headache, myalgias, and malaise, and they occur in a cyclic pattern. The parasite may also cause jaundice and anemia. P falciparum, the most malignant of the 5 species of Plasmodium, may induce kidney failure, coma, and death. Malaria-induced death is preventable if the proper treatment is sought and implemented.

P vivax and P ovale may produce a dormant form that persists in the liver of infected individuals and emerges at a later time. Therefore, infection by these species requires treatment to kill any dormant protozoan as well as the actively infecting organisms. This dormant infection is caused by the hypnozoite phase of the life cycle, which involves a quiescent liver phase, which is not typically eradicated by normal courses of antimalarials and requires treatment with primaquine to prevent further episodes of disease.

Malaria-causing Plasmodium species metabolize hemoglobin and other RBC proteins to create a toxic pigment termed hemozoin (see Media file 3).

An erythrocyte filled with merozoites, which soon will rupture the cell and attempt to infect other RBCs. Notice the darkened central portion of the cell; this is hemozoin, or malaria pigment, which is a paracrystalline precipitate formed when heme polymerase reacts with the potentially toxic heme stored within the erythrocyte. When treated with chloroquine, the enzyme heme polymerase is inhibited, leading to the heme-induced demise of non–chloroquine-resistant merozoites.

The parasites derive their energy solely from glucose, and they metabolize it 70 times faster than the RBCs they inhabit, thereby causing hypoglycemia and lactic acidosis. The plasmodia also cause lysis of infected and uninfected RBCs, suppression of hematopoiesis, and increased clearance of RBCs by the spleen, which leads to anemia as well as splenomegaly. Over time, malaria infection may also cause thrombocytopenia.

The morbidity and mortality caused by P falciparum are increased greatly over that caused by other Plasmodium species because of the increased parasitemia of P falciparum and its ability to cytoadhere. When an RBC becomes infected with P falciparum, it produces proteinaceous knobs that bind to endothelial cells. The adherence of these infected RBCs causes them to clump together in the blood vessels in many areas of the body, leading to much of the damage incurred by the parasite. Furthermore, P falciparum is able to infect RBCs of all ages, resulting in high levels of parasitemia (>5% RBCs infected). By contrast, P vivax and P ovale only infect young RBCs and thus have a relatively limited parasitemia (usually <2%).

Frequency

United States

Although cases of malaria occur in some areas of the United States in people who have not traveled outside the country and have no other known risk factors, malaria ceased to be an endemic disease to the country as of 1947. Most cases of malaria reported by those living in the United States are associated with recent travel to an endemic area. Malaria may also be transmitted at birth or trans-placentally. Rarely, malaria is transmitted through blood transfusion, needle-sharing, or organ transplant.

Travelers to forested areas of Southeast Asia and South America have become infected by Plasmodium knowlesi, a dangerous species normally found only in long-tailed and pigtail macaque monkeys (Macaca fascicularis , Macaca nemestrina). This species can cause severe illness and death in people, but, under the microscope, the parasite looks similar to the more benign P malariae and has sometimes been misdiagnosed. As P malariae infection is typically relatively mild, Plasmodium knowlesi infection should be suspected in persons residing or traveling in the above geographical areas with microscopic evidence of P malariae infection who are severely ill. Diagnosis may be confirmed via polymerase chain reaction (PCR) methods.

International

Malaria remains an enormous international medical issue, with an estimated 300-500 million cases occurring annually.¹ It is most prevalent in rural tropical areas below elevations of 1000 m (3282 ft) but is not limited to these climates. P falciparum is found mostly in the tropics and accounts for about 50% of cases and 95% of malarial deaths worldwide. P vivax is distributed more widely than P falciparum, but it causes less morbidity and mortality; however, both P vivax and P ovale can establish a hypnozoite phase in the liver, resulting in latent infection.

HIV and malaria co-infection is a significant problem across Asia and sub-Saharan Africa where both diseases may be relatively common. Evidence suggests that malaria and HIV co-infection can lead to worse clinical outcomes in both disease processes, with malarial infections being more severe in HIV-infected patients, and HIV replication increasing in malaria infection.

Mortality/Morbidity

• Internationally, as many as 2 million deaths occur annually. Of these deaths, the overwhelming majority is among children aged 5 years or younger, and 80-90% of the deaths each year are in rural sub-Saharan Africa.¹ Malaria is the world’s fourth leading cause of death in children younger than 5 years, accounting for the majority of malaria-related deaths.
• Malaria is preventable and treatable. However, the lack of prevention and treatment due to poverty, war, and other economic and social instabilities in endemic areas results in millions of deaths each year.

Race

The sickle cell trait (hemoglobin S), thalassemias, hemoglobin C, or glucose-6-phosphate dehydrogenase (G-6-PD) deficiency are protective against death from P falciparum malaria, with the former being relatively more protective than the latter three. Individuals with hemoglobin E may be protected against P vivax infection. Individuals heterozygotic for RBC band 3 ovalocytosis are at reduced risk of infection with P falciparum, Plasmodium knowlesi and, especially, P vivax malaria. West African populations lacking RBC Duffy antigen are completely refractory to infection by P vivax.

Persons living in areas of malaria endemicity may develop partial immunity to infection with time and repeated exposure. This limited immunity reduces the frequency of symptomatic malaria and also reduces the severity of infection. Immunity to malaria infection can be lost with long periods of time spent away from endemic areas with limited exposure. As a result, those individuals born in malaria-endemic regions who move abroad for work or study and then return home may be at increased risk for developing severe malaria and complications of infection.

Sex

Males and females are affected equally. However, malaria may be devastating in pregnancy to both the mother and the fetus. P falciparum is the primary species responsible for increased morbidity and mortality in pregnancy. The prevalence of malaria is higher in primigravidas than in nonpregnant women or multigravidas. Maternal complications are thought to be mediated by pregnancy associated decreases in immune function as well as placental sequestration of (P falciparum) parasites. Anemia from malaria can be more severe in pregnant women. Fetal complications include death, premature birth, anemia, and low birth weight.

Age

• All ages are affected by malaria.
• Mortality is very high in children younger than 5 years.

Clinical

History

Most patients live in or have recently traveled to an endemic area; however, a few cases are reported each year in which the patient had no history of such travel (eg, airport malaria, from imported mosquitoes). Malaria may present over 1 year after travel to an endemic area. Previously infected patients may develop relapsing malaria, a recurrence of the disease after it has been apparently cured; this form is caused by reactivation of hypnozoites (dormant liver-stage parasites) in P vivax and P ovale infections.

• Determine the patient's immune status, age, allergies, other medical conditions, other medications, and pregnancy status.
• The patient usually remains asymptomatic for a week or more after the infecting mosquito bite.
• Clinical symptoms include the following:
  • Cough
  • Fatigue
  • Malaise
  • Shaking chills
  • Arthralgia
  • Myalgia
  • Paroxysm of fever, shaking chills, and sweats (every 48 or 72 h, depending on species)
• The classic paroxysm begins with a period of shivering and chills, which lasts for approximately 1-2 hours, and is followed by a high fever. Finally, the patient experiences excessive diaphoresis, and the body temperature of the patient drops to normal or below normal.
• Many patients, particularly early in infection, do not present the classic paroxysm but may have several small fever spikes a day.
• Maintain a high index of suspicion for malaria in any patient exhibiting any malarial symptoms and having a history of travel to endemic areas.

• Less common symptoms include the following:

• Anorexia and lethargy
• Nausea and vomiting
• Diarrhea
• Headache
• Jaundice

Physical

• Physical signs that may be noted with malaria include the following:
  • Tachycardia
  • Fever
  • Hypotension
  • Signs of anemia
  • Splenomegaly
  • Icterus

Causes

• Malaria most often is caused by the bite of a female Anopheles species mosquito that is infected with species of the protozoan genus Plasmodium. The 5 most common species affecting humans are as follows:
  • P vivax: If this kind of infection goes untreated, it usually lasts for 2-3 months with diminishing frequency and intensity of paroxysms. Of patients infected with P vivax, 50% experience a relapse in a few weeks to 5 years after the initial illness. Splenic rupture may be associated with P vivax infection secondary to splenomegaly resulting from RBC sequestration. P vivax infects only immature RBCs, leading to limited parasitemia.
  • P ovale: These infections are similar to P vivax infections, although they are usually less severe. P ovale infection often resolves without treatment. Similar to P vivax, P ovale infects only immature RBCs and parasitemia is usually less than that seen in P falciparum.
  • P malariae: Those infected with this species of Plasmodium remain asymptomatic for a much longer period of time than those infected with P vivax or P ovale. Recrudescence is common in those infected with P malariae. It often is associated with a nephrotic syndrome, possibly resulting from deposition of antibody-antigen complex upon the glomeruli.
  • P knowlesi: Autochthonous cases have been documented in Malaysian Borneo, Thailand, Myanmar, Singapore, and in the Philippines, and other neighboring countries. It is thought that simian malaria cases probably also occur in Central America and South America. Patients infected with this, or other simian species, should be treated as seriously as those infected with falciparum malaria, as P knowlesi may cause fatal disease.²
  • P falciparum: The most malignant form of malaria is caused by this species. Infection with P falciparum is not limited to RBCs of a particular age and, hence, represents the highest level of parasitemia among the 5 Plasmodium species. This species also causes vascular obstruction due to its ability to adhere to endothelial cell walls. This property leads to most complications of P falciparum infection. P falciparum can cause cerebral malaria, pulmonary edema, rapidly developing anemia, and renal problems. Blackwater fever, is the darkening of the urine seen with severe RBC hemolysis resulting from high parasitemia, and is often a sign of impending renal failure and clinical decline.
• Other less common routes of infection are through blood transfusion and maternal-fetal transmission. When P vivax and P ovale are transmitted via blood, no latent hypnozoite phase occurs and treatment with primaquine is not necessary, as it is the sporozoites that form hypnozoites in infected hepatocytes.

Differential Diagnoses

Acute HIV	Mononucleosis
Babesiosis	Otitis Media
CBRNE - Plague	Pelvic Inflammatory Disease
CBRNE - Q Fever	Pharyngitis
CBRNE - Viral Hemorrhagic Fevers	Pneumonia, Bacterial
Dengue Fever	Pneumonia, Immunocompromised
Encephalitis	Pneumonia, Mycoplasma
Endocarditis	Pneumonia, Viral
Gastroenteritis	Salmonella Infection
Giardiasis	Sinusitis
Heat Exhaustion and Heatstroke	Tetanus
Hepatitis	Toxic Shock Syndrome
Hypothermia	Toxoplasmosis
Leishmaniasis	Yellow Fever
Meningitis

Other Problems to Be Considered

African trypanosomiasis
Amebiasis and amebic liver abscess
Brucellosis
Cholera
Collagen vascular disease
Enteric fever
Epidemic or louse-borne typhus
Food-borne illness or toxin
Hodgkin disease
Relapsing fever
Poliomyelitis
Schistosomiasis (acute Katayama fever)
Seizure disorder
HIV infection

Workup

Laboratory Studies

• Helpful studies include a CBC, electrolyte panel, renal function tests, pregnancy test, urinalysis, free serum haptoglobin, urine and blood cultures, and thick and thin blood smears. For those patients who may receive quinine or primaquine, a G-6-PD test should be ordered. Lumbar puncture may be indicated in patients who have encephalopathy in which the diagnosis is not clear. Rapid HIV testing may also be indicated in select cases.
• Laboratory diagnosis in the ED may be limited in hospitals that do not have personnel who are well acquainted with malaria or special tests for rapid detection of the disease.
• The British Committee for Standards in Haematology has guidelines on the laboratory diagnosis of malaria.³

Imaging Studies

• A chest radiography may be helpful if respiratory symptoms are present.
• If CNS symptoms are present, a CT scan of the head may be obtained once the patient is stable to evaluate evidence of cerebral edema or hemorrhage.

Other Tests

• Microhematocrit centrifugation
  • Using this method with the CBC tube is a more sensitive method of detection of malaria infection.
  • However, microhematocrit centrifugation does not allow the identification of the species of Plasmodium. To determine that species, a peripheral blood smear must be examined.
• Giemsa-stained thick and thin peripheral blood smears
  • These smears are the criterion standard for malaria detection and should be sent to the laboratory immediately, since malaria is a potentially life-threatening infection.
  • When reading the smear, 200-300 oil-immersion fields should be examined (more if the patient recently has taken prophylactic medication, because this temporarily may decrease parasitemia).
  • One negative smear does not exclude malaria as a diagnosis; several more smears should be examined over a 36-hour period.
• Fluorescent dyes/ultraviolet indicator tests: Several different dyes allow laboratory results to be obtained more quickly. These methods require the use of a fluorescent microscope (QBC II System, Becton-Dickinson's Quantitative Buffy Coat [QBC] method). Fluorescent /ultraviolet tests may not yield speciation information.
• Polymerase chain reaction
  • Polymerase chain reaction (PCR) is a very specific and sensitive test for determining if the species of Plasmodium are present in the blood of an infected individual. PCR is not usually available in most clinical situations.
  • PCR is also very effective at detecting the Plasmodium species present in patients with parasitemias as low as 10 parasites/mL of blood.
• Rapid diagnostic tests (RDTs) examples include Para Sight-F test (Becton Dickinson Advanced Diagnostics), ICT Malaria P.f/P.v (Binax Inc), OptiMAL pLDH (DiaMed USA, LLC), Kat-Quick (Katmedical CC), and Rapimal MT Pf Dipstick (Cellabs Pty Ltd) (dipstick tests). Note: This list is not all-inclusive; research individual tests for comparative efficacy and cost.
  • These tests are useful in detecting P falciparum infections, while some also may detect other plasmodia antigens. RDTs are based on antibody recognition of the histidine rich protein 2 (HRP-2) antigen of P falciparum and, in most cases, it has been found to be as specific as microscopy studies.⁴ A false-positive result may occur up to 2 weeks or more after treatment due to persistence of circulating antigens.
  • Some RDTs may be able to detect P falciparum in parasitemias that are below the threshold of reliable microscopic species identification.
  • RDTs are not as effective when parasite levels are below 100 parasites/mL of blood, and the test rarely is negative in those with high parasitemias. For these reasons, always confirm RDT test results with a second type of screening test when possible.
  • RDTs may not be available in the United States due to lack of FDA approval. The World Health Organization's Regional Office for the Western Pacific (WHO/WPRO) provides technical information, including a list of commercially available malaria RDTs, at Malaria Rapid Diagnostic Tests.
  • In one study, RDTs were found to perform better than microscopy under routine conditions. RDTs performed by the health facility staff were 91.7% (95% confidence interval [CI], 80.8-100%) sensitive and 96.7% (95% CI, 92.8-100%) specific. Microscopy was 52.5% (95% CI, 33.2-71.9%) sensitive and 77% (95% CI, 67.9-86.2%) specific.⁵

Treatment

Emergency Department Care

• Assess airway, breathing, and circulation; intervene as necessary. Protective airway may be indicated in cases of severe central nervous system complications.
  • If evidence of life-threatening hemolytic anemia is determined, establish large-bore intravenous (IV) lines, initiate fluid resuscitation, and administer transfusion of type-specific packed RBCs.
  • Hyponatremia likely reflects continued oral hypotonic fluid intake in the setting of hypovolemia and requires no therapy beyond rehydration.6 Overly aggressive treatment of hyponatremia may lead to death.
• Consider exchange transfusion for life-threatening complications.
• Monitor and treat hypoglycemia, as needed.
• Search for any signs of microvascular malarial complications.
• Laboratory analysis is helpful, although it is not always readily available to determine Plasmodium species, level of drug resistance, and degree of parasitemia. Obtain complete history for the laboratory.
• General hospital admission guidelines are as follows:
  • Patients with suspected or confirmed P falciparum or P knowlesi infection
  • Children
  • Pregnant women
  • Immunodeficient individuals
• Intensive care unit admission guidelines are as follows:
  • Immediate life-threatening complications present, such as coagulopathy or end-organ failure
  • Presence of signs and symptoms consistent with cerebral malaria (eg, altered mental status, repeated seizures, coma)
  • Patients who are nonimmune with a falciparum parasitemia greater than 2% or who are semi-immune with a P falciparum parasitemia greater than 5%
  • Presence of any other severe malarial complications
• A reliable, semi-immune, adult patient with a P vivax, P ovale, or P malariae infection may be treated on an outpatient basis. However, special care must be taken if P malariae is diagnosed solely on the basis of a blood smear, as it may be confused with the sometimes fatal P knowlesi, an infection that would require inpatient treatment. Those treated as outpatients should have adequate follow-up care, including daily blood smears to confirm that the treatment is effective in decreasing parasitemia.
• If the infection is caused by an unidentified species or by mixed species, treat it as if it were caused by P falciparum. In the absence of known drug sensitivities, assume that the Plasmodium species in question is chloroquine resistant. If Southeast Asia is the origin of the infection, then assume mefloquine resistance.
• If a patient is diagnosed with P falciparum malaria with a parasitemia greater than 10% or if the patient is experiencing life-threatening complications (ie, coma, respiratory failure, coagulopathy, fulminant kidney failure), then investigate exchange transfusion as a treatment option. If transfusion is undertaken, it should continue until the parasitemia falls below 5%, although the mortality benefit of this intervention has not been proven.
• Administer parenteral quinidine, quinine, or artemisinin therapy in conjunction with exchange transfusion to eradicate the protozoa from the bloodstream.
• The World Health Organization also has guidelines on treatment of malaria.⁷

Consultations

It is recommended that the emergency physician contact an infectious disease clinician or the pathologist when confronted with a possible case of malaria based upon history and physical examination to ensure proper identification and diagnosis. It is particularly recommended that the physician contact the CDC directly for any known or suspected case. Consider HIV testing if indicated.

• To aid in identification of the species of Plasmodium, also notify the pathologist of the patient’s information, including the following:
  • Determine where the patient has traveled and when the patient returned home.
  • Determine if the patient has been diagnosed with malaria ever before. If so, find out which species of Plasmodium caused the previous infection.
  • Determine what medication or prophylaxis the patient has taken, and find out when the last dose was administered.
  • Determine if the patient has a history of blood transfusion or of nonsterile needle usage.
  • Identify the date and time that the patient's blood sample was drawn and determine what condition the patient was in at that time (eg, patient was symptomatic, any periodicity of symptoms). Also provide an indication of the severity of illness.
• The Centers for Disease Control and Prevention has guidelines on the investigations of locally acquired mosquito-transmitted malaria.⁸

Medication

Antimalarial drugs have a rich history, since malaria was possibly the first human infection to be treated pharmacologically. The Chinese use of an extract from the sweet wormwood tree has led to artesemial drugs that, although expensive, are very effective. South American indigenous people have used the bark and root of the cinchona tree. The active ingredient in these medications turned out to be artemisinin and quinine, respectively, which now comprise 2 of the 4 major drug classes currently used to treat malaria. The 4 classes include quinoline-related compounds, antifolates, artemisinin derivatives, and antimicrobials.

No one drug that can eradicate all forms of the parasite's life cycle has been discovered or manufactured yet. Therefore, one or more classes of drugs often are given at the same time to combat malarial infection synergistically.

Beware of counterfeit antimalarial drugs being taken by patients that may have been purchased overseas or via the Internet. They may not contain any active ingredients at all and may contain dangerous materials.

Malaria treatment is not always straightforward. Contacting the CDC for the latest treatment guidelines and drug regimens is advised.⁹ Not all recommended treatment regimens or drugs are included below. Treatment in pregnancy and complicated malaria requires specialized drug regimens. Consult the CDC for further guidance. For the most recent CDC recommendations concerning malaria treatment, call the CDC Malaria Hotline at (770) 488-7788 (M-F, 8 am-4:30 pm, Eastern Time). For emergency consultation after hours, call (770) 488-7100 and request to speak with a CDC Malaria Branch clinician. The CDC table of guidelines for treatment of malaria in the United States can be downloaded as a pdf at Guidelines for Treatment of Malaria.

Treatment regimens are dependent on the geographic derivation of infection, the likely Plasmodium species, and the severity of disease presentation.

Antipyretics, such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), are indicated to reduce the level of discomfort caused by the infection and to reduce fever. NSAIDs should be used with caution if bleeding disorder or hemolysis is suspected.

Antimalarials can cause significant prolongation of the electrocardiograph QT interval, which can be associated with an increased risk of potentially lethal ventricular dysrhythmias. Patients receiving these drugs should be assessed for QT prolongation at baseline and carefully monitored if present. Those with normal QT intervals on ECG may not be at significant increased risk for drug-induced dysrhythmia, but caution is advised, particularly if the patient is taking multiple drug regimens, or if the patient is on other drugs affecting the QT interval.

Methemoglobinemia is a complication that may be associated with high-dose regimens of quinine the derivatives chloroquine and primaquine.10 A patient presenting with cyanosis and a normal PaO₂ on room air should be suspected of having methemoglobinemia.

Malaria vaccine production and distribution continues to be in the research and development stage.

Antiprotozoal

Chloroquine phosphate remains the DOC if the patient is infected with a nonresistant strain of Plasmodium species. For chloroquine-resistant strains, a form of quinine is the drug next in line.

Chloroquine Phosphate (Aralen)

Inhibits parasite growth by concentrating within acid vesicles of the parasite and increasing its internal pH. In addition, inhibits hemoglobin utilization and metabolism by the parasite.

• Dosing

Adult

600 mg base (=1,000 mg salt) PO immediately, followed by
300 mg base (=500 mg salt) PO at 6, 24, and 48 h
Total dose: 1,500 mg base (=2,500 mg salt) 10 mg base/kg PO immediately, followed by 5 mg base/kg PO at 6-h, 24-h, and 48-h intervals
Species not identified

Pediatric

10 mg base/kg PO, not to exceed 600 mg; then 5 mg base/kg PO; not to exceed 300 mg at 6-h, 24-h, and 48-h intervals (total 25 mg base/kg)

• Interactions

Cimetidine may increase serum levels of chloroquine (possibly other 4-aminoquinolones); magnesium trisilicate may decrease absorption of 4-aminoquinolones

• Contraindications

Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones; hypotension when given IV; impairs intradermal rabies vaccine

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Sodium channel blocking activity may increase toxicity of type Ia antidysrhythmic drugs or others with quinidinelike effects; ECG should be checked to monitor increased QRS interval effect
Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; perform periodic ophthalmologic examinations; test for muscle weakness; retinopathy, tinnitus, nerve deafness, skin eruption, headache, anorexia, nausea, vomiting, and diarrhea may occur

Clindamycin (Cleocin)

Three major drug metabolites have been shown to have strong inhibitory effects, possibly by targeting apicoplast, a chloroplast-like organelle of uncertain function.
Inhibition causes modest antimalarial effects initially but is much more potent against progeny of treated parasites. Progeny inherits nonfunctional apicoplasts, blocking production of apicoplast proteins causing a "delayed-death effect".

• Dosing

Adult

20 mg base/kg/d PO divided tid for 7 d

Pediatric

Administer as in adults

• Interactions

Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin

• Contraindications

Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile

Doxycycline (Vibramycin, Vibra-Tabs, Doryx)

May specifically impair progeny of apicoplast genes resulting in their abnormal cell division. Loss of apicoplast function in progeny treated parasites leads to slow but potent antimalarial effect.

• Dosing

Adult

100 mg PO bid for 7d

Pediatric

<8 years: Not recommended unless treatment benefit outweighs risks (consult CDC)
>8 years: 4 mg/kg/d PO divided bid for 7d

• Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy

• Interactions

Documented hypersensitivity; severe hepatic dysfunction

• Contraindications

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Primaquine

If uncomplicated infection is caused by P vivax or P ovale, important to treat patient with primaquine to prevent relapse. If species is initially unknown, then identified as P vivax or P ovale, primaquine phosphate treatment should be initiated. Binds to DNA and may disrupt parasite's mitochondria, causing major disruption in metabolic process of the parasite. Exoerythrocytic forms of the parasite are inhibited.

• Dosing

Adult

30 mg base PO qd for 14 d

Pediatric

0.5 mg base/kg PO qd for 14 d or 0.8 mg base/kg PO once/wk for 14 d

• Interactions

Coadministration with quinacrine or other quinidinelike drugs may increase toxicity (see chloroquine)

• Contraindications

Documented hypersensitivity; drugs that suppress bone marrow

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in G-6-PD deficiency and those with tendency to develop granulocytopenia

Quinine sulfate (Formula Q)

Used in chloroquine-resistant or unknown resistant infections. By increasing pH within intracellular organelles and possibly by intercalating into DNA of parasites, may inhibit growth of parasite.

• Dosing

Adult

542 mg base (=650 mg salt) PO tid for 3-7 d

Pediatric

8.3 mg base/kg (=10 mg salt/kg) PO tid for 3-7 d

• Interactions

Aluminum-containing antacids may delay or decrease quinine bioavailability when administered concurrently; cimetidine increases quinine blood levels and creates potential for toxicity; rifamycins decrease quinine concentrations by increasing hepatic clearance of quinine (effect can persist for several days after discontinuing rifamycins); concurrent administration of acetazolamide or sodium bicarbonate may increase toxicity by increasing quinine blood levels; quinine may enhance action of warfarin and other oral anticoagulants by decreasing synthesis of vitamin K-dependent clotting factors; digoxin serum concentrations may increase when digoxin administered concurrently with quinine; important to monitor digoxin levels periodically; quinidine may decrease plasma cholinesterase activity, causing decrease in metabolism of succinylcholine

• Contraindications

Documented hypersensitivity; those with optic neuritis, tinnitus, G-6-PD deficiency, or history of blackwater fever

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in G-6-PD deficiency and tendency to develop granulocytopenia; prolonged treatment or overdosing with quinine may cause cinchonism; quinine has quinidinelike activity and thus can cause cardiac dysrhythmias due to sodium channel blocking activity

Quinidine gluconate (Cardioquin, Quinalan, Quinidex, Quinora)

Indicated for severe or complicated malaria and used in conjunction with one of the following: doxycycline, tetracycline, or clindamycin. Increases pH within intracellular organelles and possibly by intercalating into DNA of parasites, may inhibit growth of parasite.

• Dosing

Adult

6.25 mg base/kg (=10 mg salt/kg) loading dose IV over 1-2 h, then 0.0125 mg base/kg/min (=0.02 mg salt/kg/min) continuous infusion for at least 24 h
Length of treatment varies by geographic origin of infection (consult CDC)

Pediatric

Administer as in adults

• Interactions

Delays absorption of digoxin; antagonizes effects of antimyasthenics; mefloquine increases risk of seizures

• Contraindications

Documented hypersensitivity; those with optic neuritis, tinnitus, G-6-PD deficiency, or history of cardiac dysrhythmias

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in G-6-PD deficiency and in patients with a tendency to develop granulocytopenia; prolonged treatment or overdosing with quinine may cause cinchonism; quinine has quinidinelike activity and can cause cardiac dysrhythmias via sodium channel blocking activity

Tetracycline (Achromycin V, Sumycin)

May specifically impair progeny of apicoplast genes resulting in their abnormal cell division. Loss of apicoplast function in progeny treated parasites leads to slow but potent antimalarial effect.

• Dosing

Adult

250 mg PO qid for 7 d

Pediatric

<8 years: Not recommended unless benefits outweigh risks (consult with CDC)
>8 years: 25 mg/kg/d PO divided qid for 7 d

• Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants

• Interactions

Documented hypersensitivity; severe hepatic dysfunction

• Contraindications

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Antimalarials

These agents inhibit growth of malarial pathogens by interfering with their stages of growth. US Food and Drug Administration has approved Coartem tablets (artemether and lumefantrine) for the treatment of acute, uncomplicated malaria infections.¹¹

Artemether 20 mg/lumefantrine 120 mg (Coartem)

Indicated for treatment of acute, uncomplicated Plasmodium falciparum malaria, the most dangerous form of malaria. Contains fixed ratio of 20 mg artemether and 120 mg lumefantrine (1:6 parts). Both components inhibit nucleic acid and protein synthesis. Artemether is rapidly metabolized into the active metabolite dihydroartenisinin (DHA), producing an endoperoxide moiety. Lumefantrine may form a complex with hemin, which inhibits the formation of beta-hematin.

• Dosing

Adult

<35 kg body weight: Use pediatric dosing
>35 kg body weight: One dose is 4 tab; take 6 doses over 3-d period as described below
Day 1: Take 1 dose, followed 8 h later by 1 dose
Day 2: Take 1 dose bid
Day 3: Take 1 dose bid

Pediatric

<5 kg: Do not administer
5 to <15 kg: 1 tab
15 to <25 kg: 2 tab
25 to <35 kg: 3 tab
>35 kg: Administer as in adults
Take 6 doses over 3-d period as described for adults

• Interactions

CYP3A4 inhibitors (including antiretroviral drugs, macrolide antibiotics, antidepressants, and imidazole antifungal agents) or CYP2D6 inhibitors (eg, flecainide, tricyclic antidepressants) may increase toxicity of lumefantrine, increasing QT prolongation; halofantrine may increase toxicity of lumefantrine, increasing QT prolongation (not for concurrent administration; administer 1 mo apart); antimalarials quinine and quinidine may have additive effects on QT interval (use caution); not approved for severe or complicated P falciparum malaria; not approved for prevention of malaria

• Contraindications

Documented hypersensitivity

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

QT prolongation may occur; avoid use in patients with congenital prolongation of QT interval (family history) and known disturbances of electrolyte imbalance (including hypokalemia or hypomagnesemia); common adverse effects include headache, dizziness, loss of appetite, and fever

Mefloquine (Lariam)

Not used in complicated malaria. Acts as a blood schizonticide and may act by raising intravesicular pH within the parasite acid vesicles. Structurally similar to quinine.

• Dosing

Adult

15 mg base/kg PO, then 10 mg base/kg PO 6-8 h later (not to exceed 1250 mg; usually 750 mg PO, then 500 mg PO at 6-8 h)
684 mg base (=750 mg salt) PO as initial dose, followed by 456 mg base (=500 mg salt) PO given 6-12 h after initial dose
Total dose = 1,250 mg salt 13.7 mg base/kg (=15 mg salt/kg) PO as initial dose, followed
by 9.1 mg base/kg (=10 mg salt/kg) PO given 6-12 h after initial dose

Pediatric

13.7 mg base/kg (=15 mg salt/kg) PO as initial dose, followed by 9.1 mg base/kg (=10 mg salt/kg) PO given 6-12 h after initial dose

• Interactions

Mefloquine administered with beta-blockers, quinine, quinidine, antiarrhythmics, TCAs, or astemizole may cause ECG abnormalities or cardiac arrest; mefloquine and chloroquine administered concomitantly may increase risk of convulsions; concomitant administration with halofantrine may cause potentially fatal prolongation of QTc interval; valproic acid administered with mefloquine can increase risk of seizures by reducing valproic acid blood levels

• Contraindications

Documented hypersensitivity; patients with seizure disorder, heart block, or psychiatric disorders

• Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use for >1 y not established; perform periodic evaluations, including LFTs, when using for prolonged periods; mefloquine may have cardiac depressant effects and antifibrillatory activity
Not recommended in infections originating in some Southeast Asian countries due to drug resistance

Artemether (Artenam)

Used only for severe or complicated malaria. Not FDA approved.

• Dosing

Adult

3.2 mg/kg IM (anterior thigh), then 1.6 mg/kg IM q24h until PO therapy is possible (never IV)

Pediatric

Administer as in adults

• Interactions

None reported

• Contraindications

Documented hypersensitivity

• Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Brainstem neurotoxicity and death in nonhuman primates have been reported; drug fever may occur

Artesunate

Experimental drug.

• Dosing

Adult

4 mg/kg PO qd for 3 d (total dose 12 mg/kg; 1 tab = 50 mg); for severe or complicated malaria, use 2.4 mg/kg IV load, then 1.2 mg/kg IV at 12 h and 24 h, then 1.2 mg/kg IV q24h until PO therapy is possible

Pediatric

Administer as in adults

Follow-up

Further Inpatient Care

• Perform thick and thin blood smears every 6-12 hours until parasitemia falls below 1% to ensure that the therapy instituted is clearing the infection.
• If parasitemia does not fall by 75% within 48 hours or if the blood is not cleared of parasites after 7 days, immediately initiate a different therapeutic regimen.
• Consult the CDC in all cases. Malaria infection may also be reportable to the local public health authority.

Further Outpatient Care

• Thick and thin blood smears should be obtained at least weekly for at least one month post treatment commencement to ensure clearance of parasitemia.

Deterrence/Prevention

• Avoid endemic regions.
• Take the proper prophylactic drugs at proper intervals if traveling to endemic regions.
• Use topical insect repellent (30-35% diethyltoluamide [DEET]), especially from dusk to dawn.
• Wear long-sleeved permethrin-coated clothing if not allergic to permethrin; spray under beds, chairs, tables, and along walls.
• Sleep under fine-nylon netting impregnated with permethrin.
• Avoid wearing perfumes and colognes.
• Seek out medical attention immediately upon contracting any tropical fever or flulike illness.
• Chemoprophylaxis is available in many different forms.
  • The drug of choice is determined by the destination of the traveler and any medical conditions the traveler may have that contraindicate the use of a specific drug.
  • Before traveling, people should consult their physician and consult the CDC's Malaria and Traveler's Web site to determine the most appropriate chemoprophylaxis.¹² Travel Medicine clinics are also a useful source of information and advice.

Complications

• Most complications are caused by P falciparum, and they may include the following:
  • Coma (cerebral malaria)
    • Defined as coma, altered mental status, or multiple seizures with P falciparum in the blood, cerebral malaria is the most common cause of death in patients with malaria. If untreated, this complication is lethal.
    • Even with treatment, 15% of children and 20% of adults who develop cerebral malaria die.
    • The symptoms of cerebral malaria are similar to those of toxic encephalopathy.
  • Seizures (secondary either to hypoglycemia or cerebral malaria)
  • Renal failure: As many as 30% of nonimmune adults infected with P falciparum suffer acute renal failure.
  • Hypoglycemia
  • Hemoglobinuria (blackwater fever)
    • Blackwater fever is the passage of dark urine, described as Madeira wine-colored.
    • Hemolysis, hemoglobinemia, and the subsequent hemoglobinuria and hemozoinuria cause this condition.
  • Noncardiogenic pulmonary edema: This affliction is most common in pregnant women and results in death in 80% of patients.
  • Profound hypoglycemia: Hypoglycemia often occurs in young children and pregnant women. It often is difficult to diagnose because adrenergic signs are not always present and because stupor already may have occurred in the patient.
  • Lactic acidosis: This occurs when the microvasculature becomes clogged with P falciparum. If the venous lactate level reaches 45 mg/dL, a poor prognosis is very likely.
  • Hemolysis resulting in severe anemia and jaundice
  • Bleeding (coagulopathy)

Prognosis

• Most patients with uncomplicated malaria exhibit marked improvement within 48 hours after the initiation of treatment and are fever free after 96 hours.
• P falciparum infection carries a poor prognosis with a high mortality rate if untreated. However, if diagnosed early and treated appropriately, the prognosis is excellent.

Patient Education

• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Malaria.

Miscellaneous

Medicolegal Pitfalls

• The emergency physician should have a high index of suspicion if a history of fever is accompanied by suggestive symptoms in a patient with a history of travel to an endemic region.
  • Failure to consider malaria in the differential of a febrile illness following such travel, even if seemingly temporally remote, can result in significant morbidity or mortality, especially in children and pregnant or immunocompromised patients.
  • Mixed infections involving more than one species of Plasmodium may occur in areas of high endemicity and multiple circulating malarial species. In these cases, clinical differentiation and decision making will be important; however, the clinician should have a low threshold for including treatment for P falciparum to avoid potentially incompletely or inadequately treating this more dangerous species.
  • Failure to recognize cases for which, due to their relatively high complication and fatality rate, inpatient treatment is highly recommended, particularly those caused by P falciparum and P knowlesi.
  • Importantly, although rare, malaria infection should be considered in patients with no history of travel who have otherwise unexplained fever, anemia, CNS dysfunction, or sepsis.
  • Individuals traveling to malarial regions must be provided with adequate information regarding prevention strategies, as well as tailored and effective antiprotozoal medications.

Special Concerns

• Pregnancy
  • Pregnant women, especially primigravid women, are up to 10 times more likely to contract malaria than nongravid women. Gravid women who contract malaria also have a greater tendency to develop severe malaria.
  • Unlike malarial infection in nongravid individuals, pregnant women with P vivax are at high risk for severe malaria, and those with P falciparum have a greatly increased predisposition for severe malaria as well.
  • For these reasons, it is important that nonimmune pregnant women in endemic areas use the proper pharmacologic and nonpharmacologic prophylaxis.
  • If a pregnant woman becomes infected, she should know that many of the antimalarial and antiprotozoal drugs used to treat malaria are safe for use during pregnancy for both the mother and the fetus. Therefore, they should be used, since the benefits of these drugs much outweigh the risks associated with leaving the infection untreated.
  • To obtain the latest CDC recommendations for malaria prophylaxis and treatment, call the CDC Malaria Hotline at (770) 488-7788 (M-F, 8 am-4:30 pm, Eastern Time). For emergency consultation after hours, call (770) 488-7100 and request to speak with a CDC Malaria Branch clinician.
• Pediatrics
  • In children, malaria has a shorter course, often rapidly progressing to severe malaria.
  • Children are more likely to present with hypoglycemia, seizures, severe anemia, and sudden death, but they are much less likely to develop renal failure, pulmonary edema, or jaundice.
  • Cerebral malaria results in neurologic sequelae in 9-26% of children, but of these sequelae, approximately one half completely resolve with time.
  • Most antimalarial drugs are very effective and safe in children, provided that the proper dosage is administered. Children commonly recover from malaria, even severe malaria, much faster than adults.

Source : http://emedicine.medscape.com/article/784065