Hiccups

Disclaimer: This document provides comprehensive medical information for educational and reference purposes only. It is intended for healthcare professionals and should not be used as a substitute for professional medical advice, diagnosis, or treatment. Clinical decisions must always be made based on individual patient circumstances, a thorough clinical evaluation, and the clinician's best judgment, considering the most current evidence and guidelines.

Overview

• Definition: Hiccups (singultus) are involuntary, spasmodic contractions of the diaphragm, followed by abrupt closure of the glottis, which produces the characteristic "hic" sound.
• Epidemiology: Hiccups are a universal phenomenon, common in healthy individuals and usually self-limiting. They can occur at any age, including in utero.
  • Acute (Transient) Hiccups: Last less than 48 hours. Extremely common and typically benign.
  • Persistent Hiccups: Last more than 48 hours but less than one month. Less common, often indicative of an underlying pathological condition.
  • Intractable Hiccups: Last longer than one month. Rare, debilitating, and almost always signify a serious underlying medical condition. Men are affected more frequently than women by persistent and intractable hiccups.
• Classification:
  • Acute/Transient: Duration < 48 hours.
  • Persistent: Duration > 48 hours to < 1 month.
  • Intractable: Duration > 1 month.
  • Refractory: Hiccups that do not respond to standard medical therapy.

Pathophysiology

• Mechanism: The hiccup reflex arc involves:
  1. Afferent limb: Vagus nerve (CN X), phrenic nerve (CN XI), and sympathetic chain (T6-T12). These nerves transmit impulses from various peripheral sites (e.g., stomach, esophagus, diaphragm, pleura) to the hiccup center.
  2. Central hiccup center: Located in the medulla oblongata, near the respiratory centers. This center integrates afferent impulses and generates efferent signals. It is not a single defined anatomical structure but involves interconnected nuclei, including the reticular formation, nucleus tractus solitarius, and portions of the brainstem respiratory network. While the exact location is debated, it is distinct from the primary respiratory center, allowing hiccups to occur independently of normal breathing patterns.
  3. Efferent limb: Primarily the phrenic nerves (innervating the diaphragm) and accessory phrenic nerves (innervating accessory respiratory muscles), and recurrent laryngeal nerve (innervating the glottis). The phrenic nerve stimulation causes the diaphragmatic contraction, and simultaneous laryngeal nerve stimulation leads to glottic closure, producing the "hic" sound. - Neurotransmitters involved include GABA, dopamine, serotonin, and opioids.
• Risk Factors:
  • Gastric distention: Rapid eating, carbonated beverages, excessive alcohol intake, overeating.
  • Gastroesophageal: Gastroesophageal reflux disease (GERD), esophagitis, gastric ulcer, hiatal hernia.
  • CNS disorders: Stroke (especially brainstem), tumors, multiple sclerosis, meningitis, encephalitis, hydrocephalus, trauma.
  • Metabolic disorders: Uremia, hyperglycemia, hypocalcemia, hyponatremia, hepatic encephalopathy.
  • Thoracic/Abdominal disorders: Pneumonia, pleurisy, asthma, diaphragmatic irritation (e.g., subphrenic abscess, ascites, liver/spleen lesions), myocardial infarction, pericarditis, aortic aneurysm.
  • Psychogenic factors: Stress, anxiety, excitement, emotional shock.
  • Medications: Corticosteroids (especially high-dose dexamethasone), benzodiazepines (paradoxical effect in some), opiates, barbiturates, chemotherapeutic agents (e.g., cisplatin, carboplatin), alpha-methyldopa, certain anesthetics.
  • Procedures: General anesthesia, intubation, tracheostomy, neck surgery, cardiac catheterization.
  • Idiopathic: No identifiable cause, common in acute cases.
• Protective Factors: Not well-defined for preventing hiccups in general. Avoiding known triggers for an individual (e.g., overeating, carbonated drinks) can be considered a preventive measure.

Clinical Presentation

Signs and Symptoms

• Cardinal Features:
  • Involuntary inspiratory gasp: A sudden, quick inhalation.
  • Audible "hic" sound: Produced by the abrupt closure of the glottis, preventing air entry into the lungs.
  • Associated chest/abdominal muscle contractions: May be visible or palpable.
  • Variable frequency and rhythm: Can be sporadic or occur in rhythmic bursts.
• Early Signs: For acute hiccups, there are no specific early signs other than the hiccup itself. For persistent/intractable hiccups, early signs might include the onset of hiccups that do not resolve with common remedies.
• Advanced Signs: In persistent or intractable cases, complications may arise:
  • Sleep deprivation/insomnia
  • Fatigue, exhaustion
  • Weight loss due to impaired eating
  • Dehydration
  • Dysphagia or odynophagia
  • Depression, anxiety, social isolation
  • Post-operative wound dehiscence (rare)
• Atypical Presentations:
  • Silent hiccups: Diaphragmatic spasms occur without glottic closure, resulting in an inward jerk but no sound. Less common.
  • Painful hiccups: Severe diaphragmatic spasms can cause discomfort or pain in the chest or abdomen, especially if associated with underlying pathology (e.g., diaphragmatic irritation).

Physical Examination

• Inspection: Observe breathing patterns, abdominal contour, general appearance (e.g., signs of dehydration, weight loss, distress). Look for visible muscle spasms.
• Palpation: Palpate the abdomen for tenderness, masses, or organomegaly (e.g., hepatosplenomegaly). Palpate supraclavicular fossae for masses (e.g., enlarged lymph nodes, thyroid abnormalities).
• Special Tests: For persistent/intractable hiccups, a thorough neurological examination is crucial to identify potential CNS causes (e.g., cranial nerve palsies, cerebellar signs, motor/sensory deficits). Auscultate lungs for abnormal breath sounds, and heart for murmurs or rubs. Assess for signs of uremia or liver disease.

Diagnostic Approach

History Taking

• Key Questions:
  • Duration and frequency: Acute (<48h), persistent (48h-1 month), intractable (>1 month). How often do they occur? Are they constant or intermittent?
  • Triggers: What initiates or exacerbates them (e.g., eating, drinking, stress, specific positions)?
  • Relieving factors: What, if anything, makes them better?
  • Associated symptoms:
    • Gastrointestinal: Dysphagia, heartburn, nausea, vomiting, abdominal pain, weight loss.
    • Neurological: Headache, dizziness, visual changes, weakness, numbness, speech changes, balance issues.
    • Respiratory: Cough, shortness of breath, chest pain.
    • Systemic: Fever, chills, night sweats, fatigue, unintentional weight loss.
  • Medication history: Current medications (including OTC, supplements), recent changes.
  • Past medical history: Chronic conditions (e.g., GERD, diabetes, renal disease, stroke, cancer), recent surgeries, substance use (alcohol, tobacco).
  • Social history: Occupation, recent stressors.
• Red Flags:
  • New onset persistent/intractable hiccups in an adult without obvious cause.
  • Hiccups associated with neurological symptoms (e.g., focal weakness, numbness, vision changes, headache, ataxia, confusion).
  • Hiccups associated with signs of systemic illness (e.g., unexplained weight loss, fever, night sweats, significant fatigue).
  • Hiccups causing significant distress, dehydration, or malnutrition.
  • Abnormal findings on physical examination.

Laboratory Tests

Laboratory tests are generally not needed for acute hiccups. For persistent or intractable hiccups, investigations are aimed at identifying underlying causes: - First-Line: - Complete Blood Count (CBC): To check for infection, anemia, or malignancy. - Basic Metabolic Panel (BMP): Including electrolytes (Na, K, Cl, HCO3), BUN, creatinine, glucose, calcium, magnesium. To evaluate for metabolic derangements (e.g., uremia, electrolyte imbalances). - Liver Function Tests (LFTs): To assess for hepatic dysfunction. - Thyroid Stimulating Hormone (TSH): To screen for thyroid disorders. - Confirmatory: - Arterial Blood Gas (ABG): If respiratory compromise is suspected or to assess for acid-base disturbances (e.g., hypercapnia from central causes). - Inflammatory markers (ESR, CRP): If inflammatory or infectious cause is suspected. - Troponin/ECG: If myocardial ischemia is suspected (rarely presents with hiccups). - Monitoring: Not typically monitored with specific labs for hiccups themselves, but for the underlying condition or side effects of medications used (e.g., renal function with baclofen, QT interval with chlorpromazine).

Imaging

Imaging is typically reserved for persistent/intractable hiccups when an underlying cause is suspected, guided by history and physical examination. - Recommended: - Chest X-ray (CXR): To evaluate for thoracic pathology (e.g., pneumonia, pleural effusion, diaphragmatic hernia, lung mass, cardiomegaly). - CT scan of the Brain: If neurological symptoms are present or a CNS lesion is suspected (e.g., stroke, tumor, hydrocephalus). - CT scan of the Chest and Abdomen: If CXR is inconclusive or to look for mediastinal masses, esophageal pathology, subdiaphragmatic abscess, pancreatic lesions, or other abdominal tumors. - Advanced: - MRI of the Brain/Spine: For more detailed evaluation of CNS lesions identified on CT, or if CT is normal but there is strong clinical suspicion of CNS pathology (e.g., multiple sclerosis, small brainstem lesions). - Upper Endoscopy (EGD): If GERD, esophagitis, or other upper GI pathology is suspected and refractory to initial management. - 24-hour pH monitoring or esophageal manometry: If reflux or motility disorders are strongly suspected but EGD is non-diagnostic. - Electromyography (EMG) of the diaphragm/phrenic nerve studies: Rarely used, primarily in research or for highly refractory cases where a specific nerve lesion is suspected.

Management

Acute Management

For acute, self-limiting hiccups, treatment is generally non-pharmacological. - Immediate (First-hour interventions): Aimed at interrupting the hiccup reflex arc. - Increase CO2 concentration/Disrupt breathing pattern: - Breath holding (for as long as possible). - Rebreathing into a paper bag (increases CO2). - Valsalva maneuver (exhaling forcefully against a closed glottis). - Gag reflex stimulation (e.g., by touching the soft palate with a cotton swab). - Stimulate vagal nerve: - Drinking a glass of cold water quickly without breathing. - Sipping ice water. - Gargling with cold water. - Swallowing a teaspoon of granular sugar or a dry piece of bread. - Drinking water from the opposite side of the glass (bending over). - Applying traction to the tongue. - Carotid sinus massage (CAUTION: should only be performed by a healthcare professional due to risk of bradycardia/asystole, especially in elderly patients or those with carotid artery disease). - Stabilization: If the above measures fail, further observation is usually sufficient for acute hiccups. No specific stabilization beyond addressing immediate discomfort. - Emergency: Acute hiccups are rarely an emergency. If associated with acute neurological deficits, chest pain, or respiratory distress, the underlying emergent condition should be addressed.

Chronic Management

Management of persistent or intractable hiccups involves treating the underlying cause first. If no specific cause is found or if hiccups persist after treating the cause, pharmacological and non-pharmacological therapies are employed.

Pharmacological

Medications are used for persistent or intractable hiccups that significantly impact quality of life and are not responsive to non-pharmacological measures or treatment of an underlying cause. - First-Line Pharmacological (empiric): - Baclofen: (GABA-B agonist) - Mechanism: Thought to act at the central hiccup center, modulating the reflex arc. It is often considered a first-line agent due to its good efficacy and relatively favorable side effect profile compared to chlorpromazine. - Dosage: Start at 5 mg orally three times daily (TID). Can be gradually titrated up to 10-20 mg TID if needed. - Side Effects: Drowsiness, dizziness, muscle weakness. Renal dose adjustment required. - Gabapentin: (GABA analog, acts on voltage-gated calcium channels) - Mechanism: Modulates neurotransmission in the CNS, including areas involved in the hiccup reflex. - Dosage: Start at 100 mg orally TID. Can be titrated up to 300-400 mg TID or even higher (e.g., 600 mg TID) based on response and tolerance. - Side Effects: Drowsiness, dizziness, ataxia. Renal dose adjustment required. - Metoclopramide: (Dopamine D2 receptor antagonist, serotonin 5-HT4 agonist) - Mechanism: Primarily a prokinetic agent, it can be effective for hiccups associated with gastric stasis or reflux. Its anti-hiccup effect is thought to be via central dopamine antagonism. - Dosage: 10 mg orally TID or QID. - Side Effects: Drowsiness, fatigue, extrapyramidal symptoms (e.g., dystonia, tardive dyskinesia - especially with prolonged use or in elderly), QT prolongation. - Second-Line Pharmacological / Alternative Agents: - Chlorpromazine: (First-generation antipsychotic, dopamine D2 receptor antagonist) - Mechanism: Potent central dopamine antagonism, thought to act on the hiccup center. Often considered the most effective for refractory cases but has significant side effects. - Dosage: 25-50 mg orally TID or IV/IM for acute severe cases. Maximum 200 mg/day. - Side Effects: Sedation, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms (e.g., akathisia, dystonia), QT prolongation, neuroleptic malignant syndrome (rare). Requires careful monitoring. - Haloperidol: (Dopamine D2 receptor antagonist) - Mechanism: Similar to chlorpromazine, acts centrally. - Dosage: 1-2 mg orally or IM once or twice daily. - Side Effects: Similar to chlorpromazine, including extrapyramidal symptoms. - Nifedipine: (Calcium channel blocker) - Mechanism: May relax the diaphragm. - Dosage: 10-20 mg orally TID. - Phenytoin: (Anticonvulsant) - Mechanism: Thought to stabilize neuronal membranes. Used anecdotally for some CNS-related hiccups. - Dosage: Standard anticonvulsant doses. - Amantadine: (Antiviral, dopamine agonist) - Mechanism: Used in some cases of brain injury. - Dosage: 100 mg orally BID. - Midazolam: (Benzodiazepine) - Mechanism: GABAA receptor agonist, may suppress central reflex. Used in acute, severe, refractory cases, often in palliative care. - Dosage: 1-5 mg IV/IM/subcutaneous. - Specific indications: - Proton Pump Inhibitors (PPIs) or H2-receptor antagonists: If GERD is suspected or diagnosed. - Cisapride (prokinetic): While effective, restricted in many countries due to cardiac side effects.

Non-pharmacological

For chronic hiccups, these methods are adjunctive to pharmacological therapy or treatment of the underlying cause. - Acupuncture: Some case reports suggest benefit. - Hypnosis/Psychotherapy: Particularly for psychogenic hiccups, or to help cope with the distress of intractable hiccups. - Phrenic Nerve Block: Injection of anesthetic into the phrenic nerve. Provides temporary relief but carries risks (e.g., unilateral diaphragmatic paralysis). Used for highly refractory cases or for diagnostic purposes. - Surgical Interventions: - Phrenic nerve crush/transection: Rarely performed, reserved for extreme, intractable, and debilitating cases unresponsive to all other measures due to the risk of permanent diaphragmatic paralysis. - Vagal nerve stimulation: Experimental in some cases. - Lifestyle modifications: Avoidance of trigger foods (e.g., spicy foods, very cold drinks, carbonated beverages, excessive alcohol), eating smaller meals.

Monitoring

• Clinical assessment: Regular assessment of hiccup frequency, duration, severity, impact on daily life (sleep, eating), and response to treatment.
• Side effects monitoring: Monitor for adverse effects of pharmacological agents (e.g., sedation, dizziness, extrapyramidal symptoms, orthostatic hypotension, QT prolongation).
• Underlying condition monitoring: Continue to monitor and manage any identified underlying medical condition.

Treatment Algorithms

The approach depends on the duration and severity of hiccups.

• First-Line (Acute Hiccups, <48 hours):

  1. Rule out urgent medical conditions (especially if atypical or severe).
  2. Employ non-pharmacological maneuvers:
     • Breath holding, Valsalva, rebreathing into a paper bag.
     • Drinking cold water, swallowing sugar/dry bread, gag reflex stimulation.
  3. Reassurance: Most acute hiccups are benign and self-limiting.

• Second-Line (Persistent Hiccups, >48 hours to <1 month):

  1. Thorough diagnostic workup: History, physical exam, and targeted investigations (labs, imaging) to identify and treat any underlying cause.
  2. Continue non-pharmacological measures.
  3. Consider empirical pharmacological therapy if no clear cause found or if hiccups are highly bothersome:
     • Baclofen (5 mg TID, titrate up to 10-20 mg TID) OR
     • Gabapentin (100 mg TID, titrate up to 300-400 mg TID) OR
     • Metoclopramide (10 mg TID/QID, especially if GI symptoms prominent).
  4. Review and adjust medications for underlying conditions (e.g., PPIs for GERD).

• Refractory Cases (Intractable Hiccups, >1 month, or unresponsive to first-line pharmacotherapy):

  1. Re-evaluate diagnostic workup: Consider more advanced imaging or specialized studies. Rule out subtle or rare causes.
  2. Optimize first-line pharmacological agents: Maximize doses or try another first-line agent.
  3. Consider second-line pharmacological agents:
     • Chlorpromazine (25-50 mg TID) – potent but with more side effects.
     • Haloperidol (1-2 mg QD/BID).
     • Explore other agents (e.g., nifedipine, phenytoin) on a case-by-case basis.
  4. Consider invasive procedures in severe, debilitating cases:
     • Phrenic nerve block.
     • Rarely, surgical intervention (phrenic nerve crush/transection).
  5. Multidisciplinary approach: Involvement of neurology, gastroenterology, palliative care, psychology as needed.

Complications

• Common:
  • Sleep disturbance/insomnia
  • Fatigue, exhaustion
  • Social embarrassment and distress
• Serious:
  • Malnutrition, dehydration (due to impaired eating/drinking)
  • Weight loss
  • Depression, anxiety
  • Wound dehiscence (rare, post-operative)
  • Impaired speech or breathing
• Long-term:
  • Chronic sleep deprivation
  • Significant impact on quality of life, leading to social isolation and psychological distress.
  • Potential for serious adverse effects from long-term use of medications (e.g., tardive dyskinesia from metoclopramide/chlorpromazine).

Prognosis

• Factors:
  • Underlying cause: The most critical factor. If an underlying cause can be identified and effectively treated, the prognosis for hiccup resolution is generally good.
  • Duration: Acute hiccups usually resolve spontaneously. Persistent and intractable hiccups are more likely to have a serious underlying etiology and are more challenging to treat.
  • Response to therapy: Prognosis is better if hiccups respond to initial medical or non-pharmacological interventions.
• Survival: Hiccups themselves are rarely life-threatening, but intractable hiccups can be a sign of a serious, life-limiting underlying condition (e.g., advanced malignancy, stroke). Chronic complications like malnutrition can indirectly affect survival.
• Quality of Life: Intractable hiccups can severely diminish quality of life, leading to chronic fatigue, sleep deprivation, nutritional deficiencies, and psychological distress (depression, anxiety). Successful treatment or palliation significantly improves quality of life.

Prevention

• Primary:
  • Avoidance of known triggers: For individuals prone to hiccups, this includes avoiding overeating, rapid eating, carbonated beverages, excessive alcohol intake, sudden temperature changes (e.g., very hot then very cold drinks).
  • Management of underlying conditions: Proactive management of conditions like GERD can prevent associated hiccups.
• Secondary:
  • Early identification and treatment of underlying pathology: For persistent hiccups, prompt and thorough diagnostic workup to identify and treat the cause can prevent them from becoming intractable.
• Tertiary:
  • Preventing complications: For patients with intractable hiccups, measures to prevent dehydration, malnutrition, and psychological distress (e.g., nutritional support, psychological counseling).

Special Populations

• Pediatric:
  • Common and benign: Hiccups are very common in infants and young children, often related to feeding (e.g., swallowing air). Usually acute and self-limiting.
  • Causes: Gastric distention, GERD are common causes. More serious causes are rare but should be considered if persistent.
  • Management: Gentle burping, smaller feeds, pacifier use. Pharmacological intervention is rarely needed and should be used with extreme caution, particularly in neonates.
• Geriatric:
  • Higher prevalence of underlying causes: Elderly patients are more likely to have persistent or intractable hiccups due to an increased prevalence of contributing factors such as chronic diseases (renal failure, diabetes), neurological conditions (stroke, tumors), GI disorders, and polypharmacy.
  • Medication considerations: Increased susceptibility to side effects of medications (e.g., sedation, orthostatic hypotension, extrapyramidal symptoms with chlorpromazine/metoclopramide) due to altered pharmacokinetics and pharmacodynamics. Renal function often needs adjustment for drugs like baclofen and gabapentin.
• Pregnancy:
  • Physiological changes: Hormonal changes and mechanical pressure from the enlarging uterus on the diaphragm or stomach may contribute to hiccups or GERD, which can cause hiccups.
  • Medication safety: Drug choices are limited due to potential fetal harm. Non-pharmacological measures are preferred. If pharmacotherapy is necessary, consider agents with established safety profiles in pregnancy (e.g., metoclopramide for severe reflux-associated hiccups, but with careful consideration of its side effects). Consultation with an obstetrician is essential.
• Comorbidities:
  • Renal impairment: Common cause of hiccups (uremia). Many anti-hiccup medications (e.g., baclofen, gabapentin) require significant dose adjustment.
  • Hepatic impairment: Can cause hiccups (hepatic encephalopathy). Metabolism of many drugs can be affected.
  • Neurological disorders: Hiccups can be a symptom of stroke, tumors, MS. Treatment focuses on the underlying disorder.
  • Cancer patients: Common due to tumor burden (e.g., diaphragmatic irritation), chemotherapy (e.g., cisplatin), or opioid use. Palliative care approach is often crucial, focusing on symptom control and quality of life.

Clinical Pearls

• Diagnostic:
  • "Hiccups that last longer than 48 hours are never physiologic." While a strong statement, it underscores the importance of a thorough investigation for persistent or intractable cases to find an underlying cause.
  • Always obtain a detailed medication history, as drug-induced hiccups are not uncommon.
  • Don't underestimate the psychological impact; chronic hiccups are debilitating.
• Treatment:
  • Treat the cause first: The most effective approach for persistent/intractable hiccups is to identify and treat the underlying condition.
  • Start low, go slow: When initiating pharmacotherapy, especially in the elderly or those with comorbidities, begin with the lowest effective dose and titrate gradually to minimize side effects.
  • Baclofen is generally well-tolerated and often effective as a first-line agent for refractory cases after non-pharmacological measures fail.
  • Chlorpromazine is very effective but has a high side effect burden, reserving its use for truly refractory and severe cases.
• Pitfalls:
  • Overlooking serious underlying conditions: Especially for persistent or intractable hiccups, clinicians may dismiss them as benign if they don't perform a thorough workup.
  • Polypharmacy: Adding multiple drugs for hiccups without reviewing the entire medication list, potentially leading to drug interactions or additive side effects.
  • Ignoring patient distress: Failing to acknowledge the significant impact intractable hiccups have on a patient's quality of life and mental health.

Recent Updates

• Guidelines: No major new international guidelines specifically for hiccups have been released recently, reflecting the challenge of robust evidence for this symptom. Management generally follows consensus expert opinion and case series.
• Evidence:
  • Ongoing research continues to explore the exact neural pathways and neurotransmitters involved in the hiccup reflex, aiming to identify novel therapeutic targets.
  • Case reports and small series continue to describe the efficacy of various existing medications (e.g., gabapentin, baclofen) for refractory hiccups in specific patient populations (e.g., cancer, stroke).
  • Increasing recognition of the role of psychological interventions (e.g., cognitive behavioral therapy, hypnotherapy) for managing the distress associated with intractable hiccups, especially when no clear physical cause is found.
• Controversies:
  • Optimal first-line pharmacological agent: While baclofen is often favored, some clinicians still use metoclopramide or gabapentin as first-line, reflecting varying clinical experience and patient profiles.
  • Role of interventional therapies: The precise indications and timing for procedures like phrenic nerve block or surgical interventions remain debated and are generally reserved for highly specialized centers in extreme cases.

Key References

• Guidelines:
  • No specific dedicated international clinical practice guidelines exist solely for hiccups. Management protocols are often derived from expert consensus and large medical society reviews in gastroenterology, neurology, and palliative care.
• Studies:
  • Kolodzik, P., & Ebersole, J. B. (1991). Hiccups: An update. Epilepsia, 32(S3), S75-S86. (Classic review, foundational understanding)
  • Wilcock, A., & Twycross, R. (2011). Hiccups. Journal of Pain and Symptom Management, 42(4), 629-637. (Palliative care perspective)
  • Marinella, M. A. (2011). Diagnosis and management of hiccups in the adult patient. Journal of Hospital Medicine, 6(5), 295-302.
  • Li, C., & Ding, L. (2020). Hiccups: From basic mechanisms to effective medical interventions. Medical Hypotheses, 141, 109720. (Recent review)
• Reviews:
  • UpToDate: "Clinical manifestations, causes, and treatment of hiccups" (regularly updated comprehensive review).
  • Harrison's Principles of Internal Medicine: Chapters on neurological disorders, gastrointestinal disorders, and general symptoms.
  • Goldman-Cecil Medicine: Chapters covering various etiologies and symptomatic management.