“Pressors” in Distributive Shock in Adults

“Pressors” in Distributive Shock in Adults

Thank you, Dr Dastmalchi, for requesting this POTD. I will review “pressors” for cardiogenic shock separately

• Vasopressors- Pure vasoconstriction without any inotropy eg Phenylephrine and Vasopressin

• Inotrope- Increase cardiac contractility à improving SV and cardiac output without any vasoconstriction eg Milrinone

• Inopressors - a combination of vasopressors and inotropes, because they lead to both increased cardiac contractility and increased peripheral vasoconstriction eg Norepinephrine, Epinephrine and Dopamine

Norepinephrine- Inopressor

• First line vasopressor in septic shock per Surviving Sepsis Guidelines

• Less arrhythmogenic than Epinephrine and Dopamine

Mechanism of action

• Stimulates alpha-1 and alpha-2 receptors

• Small amount of beta-1 agonist- modest inotropic effect

• Increased coronary blood flow and afterload

• Increases venous tone and return with resultant increased preload

Adverse effects

• Norepinephrine is considered safer than both Epinephrine and Dopamine.

• ARR of 11% compared to dopamine with NNT 9

• NE superior in improving CVP, urinary output, and arterial lactate levels compared to Epinephrine, Phenylephrine, and Vasopressin.

Indications

• First-line pressor choice in distributive shock, including both neurogenic and septic shock

• Norepinephrine as the only first-line pressor per SSC guidelines

Dosing

• Use weight-based dosing to avoid the adverse effects associated with norepinephrine use

• Weight-based dosing is based on GFR

• Norepinephrine has a rapid onset of action (minutes) and can be titrated every 2-5 minutes

Epinephrine- Inopressor

Mechanism of action

• Beta-1 and beta-2 receptors agonism à more inotropic effects than norepinephrine

• Epinephrine greatly increases chronotropy (heart rate) and thus stroke volume

• Some stimulatory effect on alpha-1 receptors

• Lower doses (1-10 mcg/min) à a beta-1 agonist

• Higher doses (greater than 10 mcg/min) à an alpha-1 agonist

Adverse effects

• Associated with an increased risk of tachycardia and lactic acidosis

• Hyperglycemia

• Increased incidence of arrhythmogenic events associated with epinephrine

• More difficult use lactate as a marker of the patient’s response to treatment

Indications

• SSC guidelines recommend epinephrine as a second-line agent, after norepinephrine

• “push-dose pressor”

• Due to beta-2 receptors agonism causing bronchodilation, epinephrine is first-line agent for anaphylactic shock

Dosing

• Guidelines for anaphylactic shock recommend an initial bolus of 0.1 mg (1:10,000) over 5 minutes, followed by an infusion of 2-15 mcg/min however associated with adverse cardiovascular events

• For septic shock start epinephrine at 0.05 mcg/kg/min (generally 3-5 mcg/min) and titrate by 0.05 to 0.2 mcg/kg/min every 10 minutes. maximum drip rate is 2 mcg/kg/min

Dopamine- Inopressor

• Fallen out of favor

• Associated with higher arrhythmogenic events

Mechanism of action

• Effects are dose-dependent

• Low doses à dopaminergic receptors à leads to renal vasodilation à increased renal blood flow and GFR although studies failed to demonstrate improved renal function with dopamine use clinically

• Moderate doses à beta-1 agonism à increased cardiac contractility and heart rate

• High doses à alpha-1 adrenergic effects à arterial vasoconstriction and increased blood pressure

Adverse Effects

• Several large, multi-center studies that demonstrate increased morbidity associated with its use

• Significantly higher rates of dysrhythmias à NNH 9

Indications

• Rescue medication when shock is refractory to other medications

Dosing

• Start at 2 mcg/kg/min and titrate to a maximum dose of 20 mcg/kg/min.

• Less than < 5 mcg/kg/min à vasodilation in the renal vasculature

• 5-10mcg/kg/min à beta-1 agonism

• 10 mcg/kg/min à alpha-1 adrenergic

Vasopressin- Vasopressor

• Add vasopressin (doses up to 0.04 units/min) to norepinephrine to help achieve MAP target or decrease norepinephrine dosage

• Restore catecholamine receptor responsiveness, particularly in cases of severe metabolic acidosis.

• pH independent

• Pure pressor à increase vasoconstriction with minimal effects on chronotropy or ionotropy

Mechanism of action

• At low doses (< 0.04 units/min) à increases vascular resistance (V1)

• No effect on heart rate and cardiac contractility

Adverse Effects

• Vasopressin has been shown to be as safe as norepinephrine at lower doses

• Increases SVR and afterload and decreases cardiac output although unclear if effect significant at lower doses

Indications

• Second line vasopressors per SSC guidelines for septic shock

• pH independent- Vasopressin in combination with epinephrine demonstrated improved ROSC in cardiac arrest patients with initial arterial pH <7.2 compared with epinephrine alone

Dosing

• Steady dose at 0.03-0.04 units/min

• Vasopressin is not titrated to clinical effect as are other vasopressors

• Think about it more as a replacement therapy and treatment of relative vasopressin deficiency

Phenylephrine- Vasopressor

• Pure pressor à increase vasoconstriction with minimal effects on chronotropy or ionotropy

• SSC guidelines does not make rated recommendations on Phenylephrine

• Limited clinical trial data

Mechanism of action

α1 agonism with peripheral vasoconstriction

Adverse Effects

• Bradycardia - decrease in heart rate mediated by the carotid baroreceptor reflex 2/2 increase in SVR

• Increases SVR and afterload and decreases cardiac output

Indications

• Patients that are susceptible to beta-adrenergic generated arrhythmia

• Push dose formulation

• Refractory shock

Dosing

0.1-2mcg/kg/min (onset: minutes, duration: up to ~20 minutes)

References:

Emdocs

LITFL

Pollard, Sacha, Stephanie B. Edwin, and Cesar Alaniz. "Vasopressor and inotropic management of patients with septic shock." Pharmacy and Therapeutics 40.7 (2015): 438.

Amlal, Hassane, Sulaiman Sheriff, and Manoocher Soleimani. "Upregulation of collecting duct aquaporin-2 by metabolic acidosis: role of vasopressin." American Journal of Physiology-Cell Physiology 286.5 (2004): C1019-C1030.

Khanna, Ashish, and Nicholas A. Peters. "The Vasopressor Toolbox for Defending Blood Pressure."

Turner, DeAnna W., Rebecca L. Attridge, and Darrel W. Hughes. "Vasopressin associated with an increase in return of spontaneous circulation in acidotic cardiopulmonary arrest patients." Annals of Pharmacotherapy 48.8 (2014): 986-991.

POTD: UTI? How to interpret your UAs and micros.

We diagnose UTIs nearly everyday, but are all of these true UTIs? Below, I will go into a quick review of what makes a UTI positive and various other tidbits. As usual, TL;DR is on the bottom of the post.

First off, patient should be instructed to provide a mid-stream sample, preferably clean-catch, however studies have shown that cleaning does not decrease contamination. 

Once collected, samples should be send immediately or refrigerated within 2 hours. This is to prevent proliferation of bacteria within the container itself. That being said, samples should still be analyzed expeditiously because refrigeration can also alter urinary leukocytes. 

Before you consider ordering any tests at all, consider this - does your patient really need testing?

UTI is a clinical diagnosis! In patients with classic symptoms for UTI (dysuria, urinary frequency, urinary urgency in the absence of symptoms that could suggest cervicitis or vaginitis), a negative dip or UA may actually falsely reassure you due to false negative results. In short, a negative result should not change your management 

Likewise, in a non-pregnant, asymptomatic patient, a false positive may lead to unnecessary treatment (besides, asymptomatic bacturia in a non-pregnant patient should not be treated anyway!!)

Now if you think a patient should be tested...

Nitrites
Nitrites are found in urine as a result of conversion of urinary nitrates to nitrites by gram negative bacteria that have been sitting in the bladder for > 4 hours. Studies have shown that they are highly specific (92-100%), but not very sensitive (19-48%). False negatives occur because nitrites require > 4 hours incubation, are not formed by some bacteria (Enterococcus faecalis) or are formed in small amounts, low urinary pH, or ingestion of foods/drugs that color the urine red. However, false positives can occur due to treatment with pyridium (phenazopyridine) and testing with strips that have been exposed to air. 

Leukocyte Esterase
Leukocyte esterase (if you remember back to your microbiology days) is produced by neutrophils and is associated with pyuria (positive requires > 10 WBC/hpf). Abnormal LE has been found to be highly sensitive (72-97%), butnot very specific (41-86%). To put that in perspective, the PPV is only 43-56%, meaning that of the patients that test positive, on the high end of the spectrum, only 56% of patients will have a culture-confirmed UTI. False positives can occur from contamination, false negatives occur from glycosuria, ketonuria, proteinuria, high urine specific gravity (increases cell lysis), vitamin C, or some oxidizing drugs (e.g. keflex, macrobid, tetracycline, gentamicin).  

What about microscopy?
So we tend to look a lot at the WBC/hpf to aid in our decision making. This is actually the less accurate method for determining pyuria - things like vaginal secretions can affect the leukocyte count. The more accurate method is hemocytometry. However, using what we have available, up to date recommends using a cut off of 8cells/microL, which corresponds to 2-5 cells/hpf. The question is how to use this information knowing that contamination can falsely increase your WBC count.

Some biostats:

• Bacteria: sensitivity 46-58%, specificity 89-94%

• > 5 WBC/hpf: sensitivity 90-96%, specificity 47-50%

Looks pretty similar to your stats for nitrites and leuk esterase, right?

There are several situations which can arise: 

• Bacteria without pyuria: absence of pyuria with a UTI are rare, so this is usually indicative of contamination and a repeat test should be done. However if the patient has symptoms, they may have an entity called "acute urethral syndrome". Likewise, if your sample is from a patient that is chronically catheterized, lack of pyuria is likely due to colonization and not infection. Keep in mind though, patients that are immunosuppressed may not have pyuria due to blunted immune response. 

• Sterile pyuria: can occur in patients that have already taken antimicrobials (your "partially treated" UTIs), contamination by sterilizing cleaning solution used to clean the urethra, vaginal leukocytes, dehydration, chronic interstitial nephritis, interstitial cystitis, uroepithelial tumors, appendicitis, diverticulitis, or atypical organisms such as Chlamydia, Ureaplasma, and TB. 

Take home points:
Don't test all urine! In a young, non-pregnant female with symptoms typical of UTI, go ahead and treat! A negative result may cloud your judgement. In other situations (pregnant female, symptomatic males, the elderly with AMS that may be due to UTI), learn to use your UA and microscopy to aid in your decision making. Figure out what can cause false negatives and false positives. Positive nitrites and positive leuks? Treat! Only have bacteria? Test again! Only have leuks? Look for other causes! In short, only use testing as an adjunct to your clinical decision making. 

TL;DR:

• Think about who you're testing! Not everyone needs a UA. 

• Nitrites are highly specific, but not sensitive

• Leukocyte esterase is highly sensitive, but not specific

• Absence of pyuria is rare in UTI, so if you see bacteria, but no pyuria, it's likely not a UTI

• Pyuria can occur in many different conditions, so if you have pyuria without bacteria, think about alternative diagnoses

Sources:
https://www.aafp.org/afp/2005/0315/p1153.html
http://epmonthly.com/article/lowly-urinalysis-avoid-common-pitfalls/
https://www.uptodate.com/contents/sampling-and-evaluation-of-voided-urine-in-the-diagnosis-of-urinary-tract-infection-in-adults
https://www.acepnow.com/article/avoiding-overdiagnosis-overtreatment-urinary-tract-infection-emergency-department/
https://emergencymedicinecases.com/uti-myths-misconceptions/

POTD: Measles (Part 2)

Part two in our two part series about measles! 

Again, TL;DR at the bottom and here's another plug for Dr. Anna Pickens' EM in 5: http://www.emdocs.net/em-in-5-measles/

This section goes over the diagnosis, management, and complications of measles. 

Transmission
Measles virus is a single-stranded, enveloped, RNA virus of the genus Morbillivirus within the family Paramyxoviridae. It is spread via respiratory droplets that may remain in the air for up to two hours. 

Clinical Presentation
Incubation period: 6-21 days (median 13 days)

Prodrome (days 2-4): fever, malaise, and anorexia followed by “the 3C’s” (conjunctivitis, coryza, and cough). This phase of infection can last up to 8 days. 

Koplik spots typically present 48 hours prior to the onset of the exanthem. They are white/gray/bluish elevations, described as “grains of salt” on an erythematous base. These are typically seen on the buccal mucosa, but may spread to the soft and hard palates. These generally last for 12-72 hours. 

Exanthem: starts 2-4 days after onset of fever. Classically is a blanching, maculopapular rash that starts on the hairline and progresses downward and outwards to the extremities. It tends to coalesce and become non-blanching with time. 

Patients will become clinically better within 48 hours of the appearance of rash, the rash will darken in color, and eventually desquamate. 

Measles may vary in severity and there are several clinical variants including: modified measles (milder symptoms) in those with pre-existing measles immunity, those who have received IVIG, and in babies with passive immunity from placental migration of immunoglobulins; atypical measles in those who have received the killed virus vaccine (not seen frequently now), which is characterized by higher and more prolonged fevers, pneumonitis, and transaminitis. Patients that are immunocompromised will also not present classically. 

Complications
Immunocompromised patients and pregnant patients are more likely to develop complications. 

Superimposed infection is common because T-cells and dendritic cells are directly infected, which leads to immune suppression that can persist for up to three years. Infections include:

• Otitis media

• Gastrointestinal (most common) - diarrhea, gingivostomatitis, appendicitis

• Pulmonary (most common cause of death) - bronchopneumonia, croup, bronchiolitis

• Neurologic

  • Encephalitis: occurs several days after rash. Patients have neurodevelopmental sequelae in 25% of cases, fatal in 15% of cases

  • Acute Disseminated Encephalomyelitis (ADEM): occurs several weeks after rash. Demyelinating disease likely due to immune response to the virus. Fatal in 10-20% of cases and survivors commonly have residual neurologic abnormalities. 

  • Subacute Sclerosing Panencephalitis (SSPE): occurs 7-10 years after infection. More likely the younger the time of infection

    • Stage I (weeks-years): insidious neurological symptoms (trouble concentrating, lethargy, personality changes, strange behavior)

    • Stage II (3-12 months): dementia, myoclonus

    • Stage III (variable): myoclonus resolves, neurologic function deteriorates leading to flaccidity/decorticate rigidity, autonomic dysfunction

    • Stage IV: death

Diagnosis:
First off, isolate your patient if you suspect measles!! Place the patient in a negative pressure room. Despite the high efficacy of MMR, there is still a 1% chance that you are not immune. As such, everybody entering the room should wear an N95 mask and the patient should wear a mask during transport. 

Test used depends on the prevalence of disease and the local governing body for infection control. In general, IgM and IgG are tested in the serum and a nasopharyngeal swab should be obtained for serological testing. False positive PCR does not rule out infection. 

Treatment:
Mainly supportive and treating any superimposed bacterial infections. In children, they tend to have low vitamin A levels, which can contribute to delayed recovery and more complications. Low vitamin A levels also causes blindness in children in the developing world. As such, children benefit from vitamin A supplementation. Ribavirin can also be considered especially for higher risk individuals (< 12 months, requiring ventilatory support, and severe immunosuppression). 

TL;DR:

• Measles is transmitted airborne, stays in the air for 2 hours

• Characterized by a prodrome of fever, malaise, coryza, conjunctivitis, and cough for 2-4 days followed by a maculopapular rash that progresses downward

• Measles can be complicated by bacterial infections. Most common cause of death is from pneumonia

• Long-term effects include severe neurological sequelae: encephalitis, acute disseminated encephalomeningitis, and subacute sclerosing panencephalitis

• Diagnose via IgM, IgG, nasopharyngal swab

• Treatment primarily supportive

• Consider vitamin A and ribavirin

Sources:
https://www.uptodate.com/contents/measles-clinical-manifestations-diagnosis-treatment-and-prevention
http://www.emdocs.net/em-in-5-measles/
http://epmonthly.com/article/ready-for-the-measles-comeback/