Toxidromes

Today's case was of a young man with a history of depression who presented with an ingestion.  He had taken an SSRI and a neurolepticin an intentional suicide attempt.  Medical history was otherwise unremarkable and he denied any coingestions.  He was admitted for monitoring with telemetry and placed on a form 1.

We talked about a number of learning points:

-When patients present to medical attention with a known or suspected overdose (or even if they just have a decreased level of consciousness) it’s important to think about toxidromes.  These are syndromes describe the physiologic consequences of taking the medication or type of medication in question.  They are important because they will likely clue you into the overdose/ingestion long before laboratory tests are available.  We discussed some of them below:

Toxidrome	Mentation	HR	RR	Temp	Skin	Entities	Treatment
Anticholinergic	Agitated	high	-	high	Dry	TCA, antihistamines	Supportive, ?cholinergics
Cholinergic	Depressed	low	-	-	Wet	Organophosphate	Atropine, pralidoxime
Sympathomimetic	Agitated	high	high	high	Wet	Cocaine, MDMA	Benzodiazepine
Opioid	Depressed	low	low	-	Normal	Morphine	Naloxone, supportive

In addition to these classic toxidromes (which can typically be ascertained just by looking at the patient) we talked about a few others:

·      Serotonin syndrome – This occurs as a result of increased serotonergic activity from medications like TCA’s, SSRI’s, and even antibiotics like linezolid.  The triad is altered mentation, neuromuscular abnormalities, and autonomic abnormalities.  Classically these patients have hyperreflexia and even spontaneous clonus.

·      Neuroleptic malignant syndrome – This occurs as a result of dopamine blockade (absolute or relative).  That means that it can occur because of an antidopaminergic medication like haloperidol, or withdrawal of Parkinsonian medications.  Contrary to popular belief, domperidone which is thought not to cross the blood-brain-barrier can cause this condition. The mnemonic for the syndrome is FARM – fever, autonomic instability, rigidity (classically lead pipe rigidity) and mental status changes.  They typically have an elevated CK from rhabdomyolysis, leukocytosis, and for whatever reason, a low serum iron level.  The treatment is withdrawal of the offending agent, and either dopamine agonists like bromocriptine, or muscle relaxants like dantrolene.

·      Alcohol withdrawal syndromes – These occur as a result of habitual alcohol use.  It should be noted that while most withdrawal syndromes are a nuisance, alcohol withdrawal can be life-threatening.  Symptoms involve autonomic changes from sympathetic surges, mental status changes (alcoholic hallucinosis, typically with tacticle hallucinations like skin-crawling), and seizures (which are always GTC’s and rarely progress to status epilepticus).

-We talked about the approach to the overdose: ensure that the airway is patent, the patient is breathing, and the blood pressure and circulatory system is functioning normally.  If this is not the case, those abnormalities need to be dealt with.  In addition to the “ABC’s” we add “D” for decontamination with things like activated charcoal, whole-bowel irrigation, and the like.  “E” gets added for elimination.  This means using medications to enhance the natural hepatic/renal metabolism of certain drugs or dialysis to remove it from the bloodstream.  Also, things like antidotes need to be considered – some drugs like acetaminophen have an antidote that prevents toxic effects.  Others, like ethanol for methanol intoxication, rely on pharmacokinetics to reduce conversion of a relatively less toxic compound to the more toxic one through competitive inhibition.

-Poison centre should generally be called for any overdose like this.  They have toxicologists on call 24 hours/day and can help you by providing rare and exceptional consequences, suggestions for supportive care, monitoring frequency, and antidotes.  Further to that, they have an important role in documentation so they should always be called even if you know what you’re doing.

Further Reading:

Boyer, E. W., & Shannon, M. (2005). The serotonin syndrome. New England Journal of Medicine, 352(11), 1112-1120.

Perry, P. J., & Wilborn, C. A. (2012). Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry, 24(2), 155-62.

Mégarbane, B. (2014). Toxidrome-based approach to common poisonings. Asia Pacific Journal of Medical Toxicology, 3(1), 2-12.

Turner, R. C., Lichstein, P. R., Peden Jr, J. G., Busher, J. T., & Waivers, L. E. (1989). Alcohol withdrawal syndromes. Journal of general internal medicine, 4(5), 432-444.

Hepatorenal Syndrome

Today's case involved a middle-aged person with cirrhosis, hepatocellular carcinoma, and a variceal upper gastrointestinal bleed.  The patient was admitted to critical care for banding of bleeding varices, and then transferred to the ward.  Shortly thereafter, her creatinine began to rise.  We spoke about the multiple possible etiologies for her acute kidney injury.

-We spoke about the creatinine itself as a renal marker.  The principle things affecting the serum creatinine are the production of it (predominantly muscle mass which is severely reduced in cirrhotic patients) and its elimination (through the kidney).  Theoretically sudden muscle catabolism would make the serum creatinine rise independently of renal function.  Additionally, the serum creatinine level must be steady state for it to be a reasonable estimate of the GFR.  If both renal arteries are clamped, the creatinine will rise slowly over several days while the GFR has actually been reduced to zero.  Likewise, if the creatinine is 1000 and the renal artery clamps are remove, the GFR returns to normal, but the creatinine will take several days to fall back down.

-Acute Kidney Injury can be divided simplistically into three general causative mechanisms.

-Pre-renal AKI occurs as a result of insufficient renal blood flow and, by definition, corrects completely when renal blood flow is restored.  This can occur most commonly as a result of volume contraction, third spacing, or impaired forward flow.  Cardiorenal syndrome and hepatorenal syndrome are, from a kidney standpoint, mainly types of pre-renal AKI.  Vascular obstructions can also lead to this phenomenon.

-Post-renal AKI occurs as a result of impaired urinary outflow from the kidneys.  With two healthy kidneys, unilateral obstruction (as in the case of nephrolithiasis) is unlikely to cause this.  Obstructions at the level of the bladder or prostate may do this.  The general treatment is restoring urine flow through catheterization or nephrostomy tubes.

-Intrinsically renal AKI is a detailed discussion, but can be simplified into which part of the kidney is experiencing the problem.  The glomerulus can be injured by a variety of mechanisms including infections (post-streptococcal, hepatitis B, hepatitis C, HIV), autoimmune processes like SLE, and neoplastic process like Hodgkin disease.  The renal tubules can be injured by medications or ischemia.  The most common tubular disorder is acute tubular necrosis, which most often results from prolonged periods of reduced renal blood flow leading to the death of tubular cells.  They slough off and create a characteristic muddy brown (heme granular) cast.  The renal parenchyma can be injured by drugs, autoimmune disease, or chrnonic infections (acute/allergic interstitial nephritis) and, although no findings are characteristic for this condition, may show WBC casts in the urine or eosinophiluria.

-Ultimately, this patient was diagnosed with hepatorenal syndrome, which is often a harbinger of a poor outcome.

-Hepatorenal syndrome can be divided into two types. Type 1 HRS is the more serious type, where large acute rises in creatinine lead to a need for either palliative management or liver transplantation.  Type 2 HRS is a less severe renal impairment wherein patients usually develop diuretic-refractory ascites.  Their creatinine slowly creeps up in contrast to type 1.

-There are a number of requirements when making a diagnosis of HRS:

·      Chronic or acute liver disease with portal hypertension and advanced liver failure

·      An acute kidney injury with a rise in creatinine of >26.5umol/L or 50% within 7 days

·      The absence of an apparent other cause – this means that shock, nephrotoxins, spontaneous bacterial peritonitis, and systemic hypovolemia must be excluded.

·      The absence of more than 50 RBC/hpf on microscopy

·      Urine protein excretion < 500mg/day

·      Lack of improvement with intravenous albumin (1g/kg) for two days

·      Withdrawal of diuretic therapy

-As we mentioned, the urinary sodium off the diuretics is typically very low (<20mmol mmol--="">

-To treat HRS, the protocol varies between critical care and medicine.  When the patients are in critical care units, they can receive intravenous norepinephrine and intravenous albumin for the combined purpose of volume expansion (with colloid likely to stay intravascular) and splanchnic vasoconstriction to improve renal blood flow.  When patients are on the wards, they are usually treated with intravenous albumin, octreotide infusions, and oral midodrine (also a vasopressor).  In the USA, a drug called terlipressin is available which can be used instead.

-Often, these patients deteriorate.  If they are not candidates for liver transplantation, then aggressive medical therapy may be their only hope – sometimes that fails and palliation/symptom control needs to be considered.  Many nephrologists do not offer dialytic therapy to these patients because their underlying liver condition is not reversible.  Occasionally, patients are transplant candidates and may be dialyzed as a bridge to transplantation.

Further Reading:

Ginès, P., & Schrier, R. W. (2009). Renal failure in cirrhosis. New England Journal of Medicine, 361(13), 1279-1290.

Image Credit: Ginès and Schrier, 2009 (above). 

Gluud, L. L., Kjaer, M. S., & Christensen, E. (2006). Terlipressin for hepatorenal syndrome. The Cochrane Library.