Anion Gap and the role of Carbonic Anhydrase: Simplified

Anion Gap and the role of Carbonic Anhydrase

Carbonic anhydrase catalyses the first part of the reversible reaction in which carbon dioxide and water are converted to carbonic acid (and vice versa):
CO2 + H2O ←→ H+ + HCO3-

In the kidney, carbonic anhydrase is found in the proximal convoluted tubule.

The equation is normally shifted to the left allowing the formed carbon dioxide to diffuse back into the systemic circulation. In the presence of a carbonic anhydrase inhibitor, such as acetazolamide, the equation is shifted to the right and more H+ and HCO3- is produced. The H+ is reabsorbed alongside chloride ions. However, the bicarbonate is passed in the urine as it is not easily absorbed in the nephron. This results in a hyperchloraemic, normal anion gap metabolic acidosis.

This effect can be used therapeutically to prevent acute mountain sickness. Whereas normally the hypoxic high altitude would stimulate ventilation resulting in a respiratory alkalosis, acetazolamide use causes net renal excretion of bicarbonate, correcting this abnormality.
With respiratory alkalosis the kidneys would physiologically excrete bicarbonate, but this takes two to three days. Acetazolamide speeds this process.
The anion gap is a simple method for discerning causes of metabolic acidosis. It relies on the fact that the concentration of cations in a solution (that is, plasma) must equal the concentration of anions. Cations have positive charge, anions have negative charge.
[Cations] = [Anions]
Most ions are unmeasured and individually have a low concentration. The measured ions in sufficient concentration are sodium, potassium, chloride and bicarbonate.

Therefore:
[Na] + [K] + [unmeasured cations] = [Cl] + [HCO3] [unmeasured anions]

And rearranging:
([Na] + [K]) - ([Cl] + [HCO3]) = [unmeasured anions] - [unmeasured cations].

In health the difference between unmeasured anions and unmeasured cations, known as the anion gap, is between 10-18 mmol/l. This value is helpful in discerning causes of metabolic acidosis, as if it is raised the acidosis is due to an unmeasured ion - such as lactate, ketones, salicylate in lactic acidosis, diabetic ketoacidosis and aspirin overdose respectively.

A normal anion gap suggests an acidosis due to bicarbonate or chloride handling - such as renal tubular acidosis, diarrhoea, ammonium chloride ingestion or, in this case, acetazolamide.

Acetazolamide is a carbonic anhydrase inhibitor which may result in a metabolic acidosis. This is not the result of an increase of unmeasured anion so therefore results in a normal anion gap. Therefore it is the best answer in this case. Other causes of a metabolic acidosis with normal anion gap are renal tubular acidosis, diarrhoea, pancreatic fistula and chloric acid (such as ammonium chloride) ingestion.

A metabolic acidosis with raised anion gap occurs in the setting of an additional unmeasured anion.
This occurs in lactic acidosis, diabetic ketoacidosis, aspirin overdose and methanol or ethylene glycol poisoning.

A metabolic alkalosis may be seen in vomiting, from other diuretics or excessive bicarbonate or antacid therapy.

Respiratory acidosis is defined by a raised pCO2 and is typically related to type 2 respiratory failure. It is seen in severe COPD, asthma, pneumonia or pulmonary oedema and hypoventilation due to sedatives, muscular disease (for example, myasthenia gravis) or chest wall trauma.

Respiratory alkalosis is seen in any cause of hyperventilation, either due to anxiety, or in hypoxic states such as asthma where adequate ventilation is preserved.

Orbital Cellulitis: Ophthalmology Emergencies

What are recommendations for patients with Orbital Cellulitis? 

Orbital cellulitis is an infection involving the contents of the orbit (fat and ocular muscles). Preseptal cellulitis and orbital cellulitis involve different anatomic sites, with preseptal cellulitis referring to infections of the soft tissues anterior to the orbital septum and orbital cellulitis referring to infections posterior to it . Although the two entities may initially be confused with one another, it is important to distinguish between them because they have very different clinical implications. Preseptal cellulitis is generally a mild condition that rarely leads to serious complications, whereas orbital cellulitis may cause loss of vision and even loss of life. Orbital cellulitis can usually be distinguished from preseptal cellulitis by its clinical features (ophthalmoplegia, pain with eye movements, and proptosis) and by imaging studies; in cases in which the distinction is not clear, clinicians should treat patients as though they have orbital cellulitis. Both conditions are more common in children than in adults.

●The most common underlying factor that leads to orbital cellulitis is acute sinusitis, particularly ethmoid sinusitis; less common causes are ophthalmic surgery and orbital trauma.

●Orbital cellulitis is often a polymicrobial infection. The most commonly identified pathogens in orbital cellulitis are Staphylococcus aureus and streptococci .

●The diagnosis of orbital cellulitis is suspected clinically and can be confirmed by contrast-enhanced computed tomography (CT) scanning of the orbits and sinuses. During the initial evaluation, it is critical to distinguish preseptal cellulitis from the more serious orbital cellulitis . It is also important to evaluate for complications of orbital cellulitis, such as subperiosteal abscess, orbital abscess, visual loss, and intracranial extension. Although both preseptal cellulitis and orbital cellulitis typically cause eyelid swelling with or without erythema, features such as ophthalmoplegia, pain with eye movements, and/orproptosis occur only with orbital cellulitis.

●The diagnosis of orbital cellulitis is made by a combination of physical examination findings (including formal assessments of extraocular movements, visual acuity, and proptosis), and radiologic assessment with CT scanning.

●We recommend that patients with suspected orbital cellulitis with any of the following features undergo a contrast-enhanced CT scan of the orbits and sinuses to confirm the diagnosis of orbital cellulitis and detect potential complications:

•Proptosis

•Limitation of eye movements

•Pain with eye movements

•Double vision

•Vision loss

•Edema extending beyond the eyelid margin

•Absolute neutrophil count (ANC) >10,000cell/microL

•Signs or symptoms of central nervous system (CNS) involvement

•Inability to examine the patient fully (usually patients less than one year of age)

•Patients who do not begin to show improvement within 24 to 48 hours of initiating appropriate therapy

●Complications of orbital cellulitis may develop rapidly and include subperiosteal and orbital abscesses, extension to the orbital apex causing vision loss, or intracranial extension causing epidural abscess or subdural empyema, intracranial abscess, meningitis, or cavernous sinus thrombosis.

●For patients with orbital cellulitis, we suggest initial empiric antibiotic treatment with parenteral broad-spectrum therapy with activity against S. aureus(including methicillin-resistant S. aureus [MRSA]), streptococci, and gram-negative bacilli; this should include vancomycin plus one of the following:ampicillin-sulbactam, piperacillin-tazobactam,ceftriaxone, or cefotaxime . If ceftriaxone or cefotaxime is employed and there is concern for intracranial extension, we suggest thatmetronidazole be added to the regimen to cover anaerobes .

●Signs and symptoms should begin to show improvement within 24 to 48 hours following the initiation of appropriate therapy; if this does not occur, repeat imaging should be performed and surgery should be considered.

●For patients with uncomplicated orbital cellulitis, we suggest that antibiotics be continued until all signs of orbital cellulitis have resolved, and for a total of at least two to three weeks (including both intravenous and oral therapy). A longer period (at least four weeks) is recommended for patients with severe ethmoid sinusitis and bony destruction of the sinus. The management of the complications of orbital cellulitis is discussed separately.

●Although initial treatment may consist of intravenous antibiotics alone, management should be in consultation with an ophthalmologist and an otolaryngologist because the physical examination requires ophthalmic and/or otolaryngologic expertise and surgery is sometimes required. The main indications for surgery are a poor response of the infection to antibiotic treatment, worsening visual acuity or pupillary changes, or evidence of an abscess, especially a large abscess (>10 mm in diameter) or one that fails to respond promptly to antibiotic treatment.

Paracetamol Poisoning: Learning Toxicology

A 42 YF ingested an unknown number of paracetamol tablets,
The following regarding paracetamol toxicity is/are true or false:

1-Histologic recovery lags behind clinical recovery and may take up to three months.

True, fact

2-Acute pancreatitis has been described in Stage 1.

False,
Stage 2

3-It is  suggested to treat with activated charcoal, 1 g/kg (maximum dose 50 g) by mouth for all patients who present within four hours .

True,
From Uptodate

4-Females are probably more protected than males via an increased supply and regeneration of glutathione and greater activity of conjugation enzymes .

False ,

Young children are probably protected via an increased supply and regeneration of glutathione and greater activity of conjugation enzymes 

5-Acute alcohol ingestion is not a risk factor for hepatotoxicity and may even be protective

True, fact
(From Uptodate)

CT or No CT? Young male with new onset seizure

SEIZURES:

24 year old male is brought to ED by his friends, who had seizure while they were having a dine out at a restaurant. Initially patient developed headache, which was gradual in onset, moderate intensity, got worse with time and resulted into fits. He had tonic clonic fits lasting 3 minutes which terminated spontaneously. Patient had post ictal state; On examination patient was found to have tongue bite and trauma to his scalp with sub galeal hematoma.
CT Brain was ordered and showed following films:

Whats the diagnosis and give rationale.

1. SOL (Astrocytoma, ganglioma, schwanoma,etc,
2. Ischemic stroke
3. Normal CT-Brain
4. Toxoplasmosis
5. No CT should be done, observe and discharge home with instructions

Discuss in comment box please..

Clinical manifestations of severe synthetic cannabinoid toxicity: An Update

Clinical manifestations of severe synthetic cannabinoid toxicity

Synthetic cannabinoids consist of a heterogeneous group of chemical compounds that act as agonists at cannabinoid receptors with 2 to 800 times the potency of delta-9 tetrahydrocannabinol (THC), the active component of cannabis (marijuana). They have emerged as a popular recreational drug in the United States and Europe. In an observational study of a multicenter, hospital-based registry of medical toxicology consultations, over two-thirds of 277 patients with single-agent exposure to synthetic cannabinoids had altered mental status including severe agitation, toxic psychosis, hallucinations, seizures, and coma [1]. Rhabdomyolysis and acute kidney injury were present in approximately 5 percent of these patients. There were three deaths, including a 17-year-old adolescent with sudden death after first-time inhalational use. Thus, unlike cannabis, synthetic cannabinoids have significant potential to cause serious and life-threatening toxicity among recreational users. 

Uptodate Sep 08, 2016

Salicylate Poisoning Mechanism: Learning Toxicology

Salicylates act directly on the respiratory center in the brainstem, causing hyperventilation and respiratory alkalosis.
In addition, salicylates interfere with the citric acid cycle limiting adenosine triphosphate (ATP) production and generating lactate. Due to increased catecholamines and an increased utilization of glucose, fatty acid metabolism increases leading to ketoacidosis.
Finally, salicylates are weak acids and contribute to the acidosis through direct proton donation. These factors contribute to increased ventilation through compensation but would not be expected to cause alkalemia (overcompensation).
Although the metabolic acidosis begins in the earliest stages of salicylate toxicity, the respiratory alkalosis predominates initially, leaving the patient with a respiratory alkalosis, metabolic acidosis, and alkalemia.

Adolescents or adults presenting with respiratory acidosis early after a salicylate overdose likely have a coingested CNS depressants, experience salicylate-induced acute lung injury, or have underlying respiratory disease.

The combination of acute respiratory alkalosis, metabolic acidosis, and acidemia is an ominous finding, indicating a life-threatening salicylate overdose.

Reference: Tintinalli

Lithium Toxicity: Learning Toxicology

A 45ym known with MDP
, on Lithium ,
He took an unknown amount of Lithium to commit suicide .

The following is/are true or false regarding Lithium toxicity :

1-Both hypothyroidism and hyperthyroidism, as well as calcium disturbances secondary to hyperparathyroidism, have been reported with lithium poisoning.

True

2-Flattened T waves, prolonged QTc intervals, and bradycardia are common.

False,
Are rare

3-Phenobarbitone is the first line therapy for seizures. 

False.
Benzodiazepine

4-Patients with acute lithium toxicity are at risk for developing nephrogenic diabetes insipidus (NDI)

False
with chronic toxicity

5-Whole bowel irrigation with polyethylene glycol (PEG) solution are not effective in patients with large acute ingestions .

False
Effective

6-Serum lithium concentrations correlate more closely with clinical signs in patients with chronic toxicity

True
For chronic toxicity

7-The syndrome of irreversible lithium effectuated neurotoxicity (SILENT) consists of prolonged neurologic and neuropsychiatric symptoms following lithium toxicity.

True,
Fact

8-Lithium poisoning is  associated with elevations in cardiac biomarkers and  left ventricular dysfunction.

False
Is not

9-Severe lithium intoxication can cause nonconvulsive status epilepticus, and encephalopathy.

True