[…] of presentation, or at weaning. [ncbi.nlm.nih.gov]

• Weakness

  The signs of IMS were weakness of proximal limb muscles and muscles innervated by motor cranial nerves, followed by the weakness of respiratory muscles and serious respiratory insufficiency. [ncbi.nlm.nih.gov]

• Fatigue

  Manifestations of Poisoning Muscarinic CNS -CNS stimulant effect leading to tremors, fatigue, drowsiness, confusion, Eye -Meiosis, blurring of vision, increased lacrimation GIT -Increased salivation, nausea, vomiting, diarrhea, Respiratory system -Respiratory [howmed.net]

  […] muscle twitching agitation Moderate signs of organophosphate exposure include: very narrowed pupils dizziness disorientation coughing and wheezing sneezing difficulty breathing drooling or excessive phlegm muscle twitching and tremors muscle weakness fatigue [healthline.com]

  When this occurs symptoms such as muscle weakness fatigue muscle cramps fasciculation paralysis tachycardia hypertension hypoglycemia anxiety headache convulsions ataxia depression of respiration and circulation tremor general weakness potential coma [intensivecarehotline.com]

  Muscle weakness, fatigue. Vomiting, diarrhoea, urination. Severe Pinpoint pupils. Confusion and agitation. Convulsions. Copious excess secretions. Cardiac arrhythmias. Collapse, respiratory depression or respiratory arrest. Coma. Death. [patient.info]

  The symptoms of organophosphate poisoning include muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis. Other symptoms include hypertension, and hypoglycemia. [en.wikipedia.org]

• Collapse

  Abstract We report a case of respiratory arrest, refractory circulatory collapse, and severe hypothermia following ingestion of an organophosphate insecticide. [ncbi.nlm.nih.gov]

  Symptoms occur within 24 hours of exposure and include collapse, breathing problems, sweating, diarrhoea, vomiting, excessive salivation, heart dysrrhythmias, extreme anxiety etc. Treatment is with atropine. [drmyhill.co.uk]

  Collapse, respiratory depression or respiratory arrest. Coma. Death. Differential diagnosis The essential features of this type of acute poisoning are those of excessive cholinergic activity. [patient.info]

  […] vomiting and diarrhea involuntary urination and defecation Emergency signs of organophosphate poisoning include: very narrowed pupils confusion agitation convulsions excessive body secretions, including sweat, saliva, mucus, and tears irregular heartbeat collapse [healthline.com]

• Unconsciousness

  On admission, she was unconscious and demonstrated convulsions, depressed respiratory movements, miosis and profuse salivation. Plasma cholinesterase concentration (842 IU.L-1) was very low and OPP was diagnosed. [ncbi.nlm.nih.gov]

  Diagnosis is usually based on a history of exposure, with characteristic signs of cholinergic excess, but can be difficult when the patient is inadvertently exposed or is unconscious or confused. [bestpractice.bmj.com]

  Both fell unconscious while sitting on a park bench. A first responder to the scene also became contaminated and had symptoms of organophosphate poisoning. All three survived after hospital treatment. [en.wikipedia.org]

• Respiratory Distress

  An autopsy confirmed the presence of adult respiratory distress syndrome and acute tubular necrosis. [ncbi.nlm.nih.gov]

• Cough

  Inhalation Eye contact• Cough • Irritation• Difficulty in breathing • Pain• Bronchitis • Lacrimation• Pneumonia • Miosis • Blurring vision • Photophobia 6. All the clinical features infrom head to Toe 7. [slideshare.net]

  The patient can have wheezing, chest tightness, and productive cough. The bronchorrhea can be significant with frothy and/or bloody sputum and severe pulmonary oedema. Toxic myocardiopathy has been noted in some severe OP poisonings. [emergencymedicalparamedic.com]

  Rapid-onset eye and/or skin irritation and choking/coughing/wheezing. Is chemical exposure still a possibility? Unexplained sudden death in a healthy adult. Unexplained reduction in level of consciousness. [patient.info]

  […] pupils impaired, blurry vision stinging eyes runny nose watery eyes excess saliva glassy eyes headache nausea muscle weakness muscle twitching agitation Moderate signs of organophosphate exposure include: very narrowed pupils dizziness disorientation coughing [healthline.com]

• Rhinorrhea

  Central nervous system signs and symptoms Miosis (unilateral or bilateral) Headache Restlessness Convulsions Loss of consciousness Coma Respiratory signs and symptoms Rhinorrhea (perfuse watery runny nose) Bronchorrhea (excessive bronchial secretions) [emergency.cdc.gov]

  Sweating and rhinorrhea also frequently are present. Weakness, fasciculations, incoordination, and GI distress all are markers of a worsening poisoned condition. Pulmonary oedema may be a late manifestation of OP poisoning. [emergencymedicalparamedic.com]

  sweating, salivation, lacrimation, rhinorrhea, bronchorrhea); symptoms of a worsening state include muscle fasciculations, weakness, tremor, vomiting, abdominal cramps, and diarrhea. [clinicaladvisor.com]

• Vomiting

  On the same day the patient also developed severe upper abdominal pain along with nausea and vomiting. [ncbi.nlm.nih.gov]

  and Ashish Bhalla, M.D. 2 Citing Articles A 15-year-old boy who lived with his family on a farm presented to the emergency department with a 1-day history of vomiting, diarrhea, and altered sensorium. [nejm.org]

• Diarrhea

  Atropine sulphate was administered intravenously in repeated doses to all children with bradycardia, diarrhea, salivation, and miosis. [journals.lww.com]

  and Ashish Bhalla, M.D. 2 Citing Articles A 15-year-old boy who lived with his family on a farm presented to the emergency department with a 1-day history of vomiting, diarrhea, and altered sensorium. [nejm.org]

  Organophosphate poisoning Pathology Type Toxin Cause(s) Exposure to pesticides Symptoms Excessive salivation, excessive tear production, uncontrolled or excessive urination, diarrhea, nausea, vommiting. [house.wikia.com]

  Excess acetylcholine produces a predictable cholinergic syndrome consisting of copious respiratory and oral secretions, diarrhea and vomiting, sweating, altered mental status, autonomic instability, and generalized weakness that can progress to paralysis [emergency.cdc.gov]

• Nausea

  On the same day the patient also developed severe upper abdominal pain along with nausea and vomiting. [ncbi.nlm.nih.gov]

  Organophosphate poisoning Pathology Type Toxin Cause(s) Exposure to pesticides Symptoms Excessive salivation, excessive tear production, uncontrolled or excessive urination, diarrhea, nausea, vommiting. [house.wikia.com]

  Gastrointestinal symptoms such as nausea, vomiting, and fecal and urinary incontinence, cardiac symptoms such as hypotension, bradycardia, and tearing, drooling, and miosis Children younger than what age are at the greatest risk for accidental poisonings [quizlet.com]

  Manifestations of Poisoning Muscarinic CNS -CNS stimulant effect leading to tremors, fatigue, drowsiness, confusion, Eye -Meiosis, blurring of vision, increased lacrimation GIT -Increased salivation, nausea, vomiting, diarrhea, Respiratory system -Respiratory [howmed.net]

  Bradycardia (decreased heart rate) – late (decreased heart rate) Hypotension (low blood pressure) – late (low blood pressure) Arrhythmias Dysrhythmias (prolonged QT on EKG, ventricular tachycardia) Gastrointestinal signs and symptoms Abdominal pain Nausea [emergency.cdc.gov]

• Abdominal Pain

  Abdominal pain was reported by 65.3% of the patients. Abdominal ultrasonography was performed in 22 patients who complained of abdominal pain as a leading symptom. Among these, 63.6% were found to have abdominal free fluid. [ncbi.nlm.nih.gov]

  […] blood pressure) Bradycardia (decreased heart rate) – late (decreased heart rate) Hypotension (low blood pressure) – late (low blood pressure) Arrhythmias Dysrhythmias (prolonged QT on EKG, ventricular tachycardia) Gastrointestinal signs and symptoms Abdominal [emergency.cdc.gov]

• Upper Abdominal Pain

  On the same day the patient also developed severe upper abdominal pain along with nausea and vomiting. [ncbi.nlm.nih.gov]

• Hypersalivation

  She had vomiting, excessive retching, diarrhoea, miosis, hypersalivation and bilateral crepitation on chest during admission. After immediate resuscitation, atropinization was done and it required total of 36 milligram. [ncbi.nlm.nih.gov]

  The most frequent clinical signs were meiosis, change in mental status, hypersalivation, agitation and fasciculations (Table 2 ). [ccforum.biomedcentral.com]

  Clear chest None Observed 1 h, then discharged 3 Medical Registrar Coordinating medical care, 3–4 h with patient Hypersalivation HR 97/min, BP 135/94. [academic.oup.com]

  Within 4 h of ingestion of the insecticide, symptoms of acute OP poisoning developed and the patient was admitted to the hospital suffering from severe abdominal cramps, hypersalivation, and excessive sweating. [mjdrdypu.org]

  Signs and symptoms include lacrimation, hypersalivation, bronchial hypersecretion and bronchoconstriction, urination and defecation, skeletal muscle fasciculation and twitching, ataxia, respiratory failure, convulsions, hypothermia and death. [web.archive.org]

• Hypotension

  A 19-year-old man with an alleged history of suicidal ingestion of a pesticide presented with drowsiness and was found to have constricted pupils, hypotension and bradycardia. [ncbi.nlm.nih.gov]

  On initial assessment, he was drowsy and had tachypnea and hypotension. Auscultation of the lungs revealed diffuse crepitations. His pupils were reactive, equal in size, and mildly constricted (4 mm in diameter). [nejm.org]

  While the AKI may have been caused by a period of hypotension, there was speculation that it may have been directly caused by the organophosphate. [renalfellow.blogspot.com]

• Tachycardia

  On Holter monitoring, episodic tachycardia and ST-T changes were observed in four, QT prolongation in three, and episodic bradycardia in two. [ncbi.nlm.nih.gov]

  Tachycardia and mydriasis must not be used to limit or to stop subsequent doses of atropine. The main concern with OP toxicity is respiratory failure from excessive airway secretions. [openanesthesia.org]

• Hypertension

  Each OP poisoning patient was frequency-matched to 4 control patients based on age, sex, index year, and comorbidities of diabetes, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, coronary artery disease, and stroke (N 35,696). [ncbi.nlm.nih.gov]

  […] respiratory rate/depth) – early (increased respiratory rate/depth) Bradypnea (decreased respiratory rate) – late (decreased respiratory rate) Cardiovascular signs resulting from blood loss Tachycardia (increased heart rate) – early (increased heart rate) Hypertension [emergency.cdc.gov]

  Bradycardia is the usual cardiac sign, but there can be tachycardia and hypertension from nicotinic, sympathetic stimulation. [emergencymedicalparamedic.com]

  Table 1 Effects of acute organophosphate poisoning Muscarinic effects Nicotinic effects CNS effects Bradycardia Tachycardia Agitation Bronchospasm Hypertension Confusion Bronchorrhoea Muscle fasciculation Psychosis Sweating Muscle cramps Delirium Salivation [academic.oup.com]

• Muscle Twitch

  […] include: very narrowed pupils dizziness disorientation coughing and wheezing sneezing difficulty breathing drooling or excessive phlegm muscle twitching and tremors muscle weakness fatigue severe vomiting and diarrhea involuntary urination and defecation [healthline.com]

  twitching• Bradycardia• Cardiac arrhythmia• Diarrhoea• Vomiting• Salaivation• Tenesmus• Miosis• Lacrimation• Blurred vision 4. [slideshare.net]

  Breathing may become difficult, and muscles twitch and become weak. Rarely, shortness of breath or muscle weakness is fatal. [merckmanuals.com]

  Diazepam is used for controlling muscle twitching and convulsions. The antidote pralidoxime acts by splitting the phosphate–acetylcholinesterase bond and regenerating active acetylcholinesterase. [academic.oup.com]

• Muscle Cramp

  Bronchospasm Hypertension Confusion Bronchorrhoea Muscle fasciculation Psychosis Sweating Muscle cramps Delirium Salivation Muscle weakness Convulsions Lacrimation Respiratory paralysis Coma Vomiting Diarrhoea, miosis Muscarinic effects Nicotinic effects [academic.oup.com]

  When this occurs symptoms such as muscle weakness fatigue muscle cramps fasciculation paralysis tachycardia hypertension hypoglycemia anxiety headache convulsions ataxia depression of respiration and circulation tremor general weakness potential coma [intensivecarehotline.com]

  The symptoms of organophosphate poisoning include muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis. Other symptoms include hypertension, and hypoglycemia. [en.wikipedia.org]

• Miosis

  No miosis or wheeze None Discharged 10 ED Porter Portering, 30 min in room with patient Giddiness HR 60/min, BP 132/79. No miosis or wheeze None Discharged HR, heart rate; BP, blood pressure; ECG, electrocardiograph; PEFR, peak expiratory flow rate. [academic.oup.com]

  Human poisoning due to amitraz may be misdiagnosed as organophosphate/carbamate (OPC) toxicity, since amitraz poisoning shares several clinical features (miosis, bradycardia and hypotension) encountered with OPC poisoning. [ncbi.nlm.nih.gov]

• Lacrimation

  Clinical features of organophosphate poisoning are defecation, urination, miosis, bronchorrhea, emesis, lacrimation and salivation. Spontaneous abortion reported some when in pregnant patients. [ncbi.nlm.nih.gov]

  SLUDGE stands for: salivation, lacrimation, urination, defication, GIT disturbances, and emesis. [emergencymedicalparamedic.com]

  Inhalation Eye contact• Cough • Irritation• Difficulty in breathing • Pain• Bronchitis • Lacrimation• Pneumonia • Miosis • Blurring vision • Photophobia 6. All the clinical features infrom head to Toe 7. [slideshare.net]

  salivation SLUDGE: salivation, lacrimation, urination, defaecation, emesis INVESTIGATIONS butyrylcholinesterase or acetylcholinesterase activity MANAGEMENT Resuscitation aspiration/bronchospasm/seizures may necessitate airway protection and mechanical [lifeinthefastlane.com]

• Blurred Vision

  A 42-year-old pregnant woman (26 weeks of gestation, G(4)P(0 3)) presented at the emergency department with a two-hour history of dizziness, blurred vision and repeated vomiting. [ncbi.nlm.nih.gov]

  Signs and Symptoms Muscarinic signs (SLUDGE) salivation, lacrimation, urination, diaphoresis, gastrointestinal upset, emesis and progressing to bronchospasm, bronchorrhea, blurred vision, bradycardia or tachycardia, hypotension, confusion, and shock. [openanesthesia.org]

  Signs of specific muscarinic stimulation include those which are indicative of parasympathetic stimulation such as: miosis, blurred vision, increased secretions, decreased heart rate, bronchoconstriction, nausea, vomiting, abdominal cramps, incontinence [emergencymedicalparamedic.com]

  Painful, blurred vision. Runny nose and eyes. Excess saliva. Eyes looking 'glassy'. Headache. Nausea. Mild muscle weakness. Localised muscle twitching. Mild agitation. Moderate Pinpoint pupils, conjunctival injection. Dizziness, disorientation. [patient.info]

• Incontinence

  Faecal incontinence is a debilitating condition. Sacral neuromodulation may have a role in the treatment of faecal incontinence. [ncbi.nlm.nih.gov]

  Gastrointestinal symptoms such as nausea, vomiting, and fecal and urinary incontinence, cardiac symptoms such as hypotension, bradycardia, and tearing, drooling, and miosis Children younger than what age are at the greatest risk for accidental poisonings [quizlet.com]

  […] late (decreased heart rate) Hypotension (low blood pressure) – late (low blood pressure) Arrhythmias Dysrhythmias (prolonged QT on EKG, ventricular tachycardia) Gastrointestinal signs and symptoms Abdominal pain Nausea & and vomiting Diarrhea Urinary incontinence [emergency.cdc.gov]

  Signs of specific muscarinic stimulation include those which are indicative of parasympathetic stimulation such as: miosis, blurred vision, increased secretions, decreased heart rate, bronchoconstriction, nausea, vomiting, abdominal cramps, incontinence [emergencymedicalparamedic.com]

  A wide range of other symptoms may also be noted, including incontinence, defecation, tachycardia, bradycardia, hypertension, cramping of skeletal muscles, bronchospasm, and pulmonary edema. [clinicaladvisor.com]

• Cesarean Section

  She recovered within 7 days and delivered a healthy baby 12 weeks later (Apgar score 9 and 10) by elective cesarean section. The child showed no signs or symptoms of organophospate, atropine or pralidoxime exposure. [ncbi.nlm.nih.gov]

• Seizure

  Abstract After cutaneous application of the organophosphate insecticide Diazinon for pubic lice, our patient had symptoms of cholinergic excess, lost consciousness, and had a seizure. [ncbi.nlm.nih.gov]

  […] miosis, bronchorhea, bradycardia, emesis, lacrimation, salivation SLUDGE: salivation, lacrimation, urination, defaecation, emesis INVESTIGATIONS butyrylcholinesterase or acetylcholinesterase activity MANAGEMENT Resuscitation aspiration/bronchospasm/seizures [lifeinthefastlane.com]

  Benzodiazepines are used for seizures. Prophylactic diazepam may help prevent neurocognitive sequelae after moderate to severe organophosphate poisoning. [merckmanuals.com]

  CNS effects vary from alertness at low doses to seizures and coma at high doses. At low doses, anticholinesterase drugs cause a predominantly vagal response in the heart, with bradycardia and decreased cardiac output. [derangedphysiology.com]

• Confusion

  Nicotinic and muscarinic Ach receptors in theAch receptors in the CNS sympathetic system• Confusion • Excessive sweating• Agitation Other effects• Respiratory failure• Ataxia • hyperglycaemia• convulsion • Acute pancreatitis 5. [slideshare.net]

  Diagnosis is usually based on a history of exposure, with characteristic signs of cholinergic excess, but can be difficult when the patient is inadvertently exposed or is unconscious or confused. [bestpractice.bmj.com]

  Confusion, anxiety, restlessness and toxic psychosis can occur and there have been reports of memory loss and depression. The benefits and limitations of atropine as a treatment strategy in organophosphate poisoning. [emergencymedicalparamedic.com]

  Manifestations of Poisoning Muscarinic CNS -CNS stimulant effect leading to tremors, fatigue, drowsiness, confusion, Eye -Meiosis, blurring of vision, increased lacrimation GIT -Increased salivation, nausea, vomiting, diarrhea, Respiratory system -Respiratory [howmed.net]

  Abou-Donia's latter point is particularly important, as some of the fume events investigated saw one pilot react badly to the neurotoxins while the other was apparently unaffected, which led to confusion. [flightglobal.com]

• Headache

  The symptoms included headaches, loss of memory and numbness in his limbs. He was grounded on full pay in September 2011, and consultation with a neurologist in Amsterdam followed. [flightglobal.com]

  Sometimes the farmer just has a bit of a headache, feels unusually tired or finds he can't think clearly. This may just last a few hours to a few days and the sufferer recovers completely. [drmyhill.co.uk]

  Central nervous system signs and symptoms Miosis (unilateral or bilateral) Headache Restlessness Convulsions Loss of consciousness Coma Respiratory signs and symptoms Rhinorrhea (perfuse watery runny nose) Bronchorrhea (excessive bronchial secretions) [emergency.cdc.gov]

  Dizziness, headache and the SLUDGE syndrome of salivation, lacrimation, urination, defecation, GI upset and emesis are some of the common early symptoms reported. Sweating and rhinorrhea also frequently are present. [emergencymedicalparamedic.com]

  These solvents can lead to symptoms too, including headache and nausea. Lipophilic compounds can cause delayed or persistent toxicity as they slowly move out of the tissues. Remember that accurate, contemporaneous notes are essential. [patient.info]

• Tremor

  The presence of rigidity, tremors, dystonia and chorea were assessed daily till discharge using modifications of the Unified Parkinson's Disease rating scale and the Tremor rating scale. [ncbi.nlm.nih.gov]

  Manifestations of Poisoning Muscarinic CNS -CNS stimulant effect leading to tremors, fatigue, drowsiness, confusion, Eye -Meiosis, blurring of vision, increased lacrimation GIT -Increased salivation, nausea, vomiting, diarrhea, Respiratory system -Respiratory [howmed.net]

  Observe: Muscarinic features Nicotinic features Diarrhoea Urination Miosis Bronchospasm Bronchorrhoea Emesis Lachrymation Salivation Fasciculations Tremor Weakness Respiratory muscle weakness Bradycardia (tachycardia may be present) Hypotension Agitation [derangedphysiology.com]

• Lethargy

  A 12-day-old infant girl was admitted with increasing lethargy and respiratory distress. [ncbi.nlm.nih.gov]

  Miosis (73%), excessive salivation (70%), muscle weakness (68%), and lethargy (54%) were the most common abnormal signs; 49% and 22% of patients had tachycardia and seizures, respectively, and 38% of children had respiratory insufficiency that required [pediatrics.aappublications.org]

  CNS toxicity is common, sometimes with seizures and excitability and often with lethargy and coma. Pancreatitis is possible, and organophosphates may cause arrhythmias such as heart block and QTc interval prolongation. [merckmanuals.com]

  lethargy, coma) are more commonly observed, along with flaccid muscle weakness, miosis, and excessive salivation. Conversely, bradycardia, muscular fasciculations, lacrimation, and sweating are less common than in adult patients. [clinicaladvisor.com]

See Workup. Treatment begins with decontamination. Airway control and oxygenation are paramount. The mainstays of pharmacological therapy include atropine, pralidoxime (2-PAM), and benzodiazepines (eg, diazepam). [emedicine.medscape.com]

• Narrow QRS Complex

  We report a case of organophosphate poisoning associated with atrial fibrillation, right bundle branch block, QT interval prolongation, and intermittent narrow QRS complexes that were most likely due to automaticity from the region of the left posterior [ncbi.nlm.nih.gov]

• Right Bundle Branch Block

  We report a case of organophosphate poisoning associated with atrial fibrillation, right bundle branch block, QT interval prolongation, and intermittent narrow QRS complexes that were most likely due to automaticity from the region of the left posterior [ncbi.nlm.nih.gov]

• Pancreatic Necrosis

  We report two cases of severe acute pancreatitis complicated by pancreatic necrosis and retroperitoneal sepsis in which the diagnosis was obscured by the systemic effects of organophosphate toxicity. [ncbi.nlm.nih.gov]

The aim of the study was to assess the impact of plasmapheresis treatment in the management of three pediatric patients with organophosphate poisoning who did not respond to standard treatment. [ncbi.nlm.nih.gov]

Awareness of this complication should prompt earlier investigation because early diagnosis coupled with timely therapeutic measures may improve patient prognosis. [ncbi.nlm.nih.gov]

Acute kidney injury as a direct complication of organophosphate poisoning has rarely been described and its etiology is unclear. [ncbi.nlm.nih.gov]

The lack of diagnostic support for infection coupled with the expanded exposure history allowed identification of the underlying etiology of acute pesticide poisoning. [depts.washington.edu]

The exact etiology, incidence, and risk factors associated with IMS are not well understood, but IMS is recognized as a disorder of neuromuscular junctions. IMS occurs when a person has a prolonged and severe inhibition of AChE. [en.wikipedia.org]

Describes everything you need to know about Organophosphates and Carbamates Extensively covers pesticides, nerve agents, therapeutic drugs, and flame retardants Describes epidemiology of the world's major disasters involving Organophosphates and Carbamates [books.google.de]

International Epidemiological Association, 29, 510 – 515. Goldstein, G., Beers, S.R., Morrow, L.A., Shemanski, W.J., & Steinhauer, S.R. ( 1996 ). A preliminary neuropsychological study of Persian Gulf War veterans. [doi.org]

Part 2: An Epidemiological Perspective". [web.archive.org]

The pathophysiological basis for the clinical manifestations of OP poisoning is inactivation of the enzyme, acetylcholinesterase at the peripheral nicotinic and muscarinic and central nervous system (CNS) nerve terminals and junctions. [ncbi.nlm.nih.gov]

Because of this, paramedics must thoroughly understand the pathophysiology and signs and symptoms of organophosphate poisoning. Organophosphates are found in pesticides, herbicides and nerve gas. [emergencymedicalparamedic.com]

Specifically, they aim to define the pathophysiology of IMS, which was initially described in 1987 as an illness occurring after the resolution of acute cholinergic crises and associated with proximal muscle weakness [ 2 ]. [journals.plos.org]

Continuous pralidoxime methylsulphate infusion with atro pine did not prevent the development of IMS, most likely due to the delayed treatment and insufficient oxime dose but also because of chemical structure and lipophilicity of ingested OPI. [ncbi.nlm.nih.gov]

If done, the trachea is intubated beforehand to prevent aspiration. [merckmanuals.com]