Use of Vasoactive Medicines for Septic Shock in Pediatric Advanced Life Support (PALS)

All that follows are direct quotes from the 2011 edition of the Pediatric Advanced Life Support Manual (1) except for text in brackets [comments] which is my commentary.

Vasoactive agents are not routinely indicated for the management of hypovolemic shock. Moribund children with profound hypovolemic shock and hypotension may require short-term administration of vasoactive agents such as epinephrine to restore cardiac contractility and vascular tone until adequate fluid resuscitation is provided. [An example of this would be when the infant or child’s mean blood pressure falls below a level that endangers cardiac perfusion and thus heart pumping function.]  [For a great detailed video how to on pulse dosing of epinephrine, see Another Great YouTube Video from Dr. Mellick–Pediatric Pulse Dose Pressor Administration (2) ]

Managing fluid refractory septic shock (pp 101 + 102)

If severe shock persists despite rapid aggressive administration of isotonic crystalloid in the first hour, start treatment for fluid refractory septic shock as follows:

  • Establish arterial and central venous access if not already obtained.
  • Administer vasoactive therapy to improve tissue perfusion and blood pressure.
  • Administer additional fluid boluses of 20 mL per kilogram isotonic crystalloid and consider giving up colloid containing fluid.
  • If the hemoglobin concentration is less than 10 g/dL, consider transfusion to increase 02 carrying capacity.
  • Consider early assisted ventilation with supplementary 02 and PEEP as needed.   [Personal Note: Intubation and early assisted ventilation can markedly decrease the work of breathing and hence reduce metabolic demand. But all RSI meds may drop blood pressure (through lysis of sympathetic surge). Blood pressure may also drop from the decreased preload that occurs with positive pressure ventilation.]

Medication therapy is directed by assessment of blood pressure (including pulse pressure), evaluation of vascular resistance (including peripheral pulses, temperature and perfusion), and SCV 02 if available. It is not always clear from the physical examination whether a child has vasodilatation or vasoconstriction. For example some children with cool extremities may have vasodilatation but be poorly perfused because of low stroke volume and were cardiac function. [However, use of bedside echo may be able to help make that distinction.] The reasons for specific drugs selection according to the type of shock are described below

“Warm” shock

Norepinephrine* is the vasoactive agent of choice for the child with fluid refractory septic shock presents in basil dilated (“warm”) shock with poor perfusion or hypotension. Norepinephrine is chosen for its potent health the adrenergic constricting effects which can raise diastolic pressure by increasing SVR. It is also chosen for its ability to increase cardiac contractility with little change in heart rate. This can restore blood pressure by increasing SVR, venous tone, and stroke volume.

A vasopressin infusion may be useful in the setting of norepinephrine refractory shock. Vasopressin antagonizes the mechanisms of sepsis mediated vasodilatation yaks synergistically with endogenous and exogenous catecholamines in stabilizing blood pressure but it has no effect on cardiac contractility.

Normotensive shock

Dopamine is the preferred vasoactive agent for the child with fluid refractory septic shock who presents with impaired perfusion but adequate blood pressure dopamine has variable affects that are dose-dependent. At low doses dopamine improves splanchnic and renal blood flow. An intermediate doses it improves contractility. At higher doses SVR is increased. If the child’s perfusion does not rapidly improve with the dopamine infusion, start and epinephrine or norepinephrine infusion. On the basis of the child’s pulse pressure and clinical examination, use epinephrine if the child has normal to client vascular resistance; use norepinephrine if the child has low vascular resistance. Vasodilators may be useful for improving tissue perfusion in normotensive children who have high SVR smite fluid resuscitation and initiation of inotropic support.

If poor perfusion persists despite dopamine, consider adding Miller known or Nitro + to the treatment regimen. Miller known as a phosphodiesterase inhibitor that has both inotropic and vasodilator effects. Hydroperoxide is a pure vasodilator. You may also consider dobutamine. Dobutamine provides both inotropic and vasodilator effects but it often causes significant tachycardia in may produce a substantial decrease in SVR, with resulting hypotension.

“Cold” shock

Epinephrine is the preferred vasoactive agent to treat “cold” shock. It has potent inotropic effects that improves stroke volume. The epinephrine dose can be titrated to support blood pressure and systemic perfusion. Have low infusion doses, epinephrine can lower SVR (from its beta-adrenergic effects). At higher infusion rates, epinephrine can increase SVR (from its alpha adrenergic action). And infusion dose of epinephrine in the range of greater than or equal to 0.3 µg per kilogram per minute usually produces a predominant alpha adrenergic action. Epinephrine may increase lactate levels by stimulating lactate production in the skeletal muscle.

A combination of dobutamine and norepinephrine may also be considered, based on its effectiveness in adults with septic shock the norepinephrine infusion counterbalances the tendency of dobutamine to cause an excessive decline in SVR and appears to better restore splanchnic perfusion.

Correction of adrenal insufficiency

A child and septic shock who is fluid refractory and dopamine dependent or norepinephrine dependent may have adrenal insufficiency. Possible, obtain a baseline cortisol level. In the absence of prospective data defining adrenal insufficiency based on cortisol level, adrenal insufficiency may be present if a random cortisol level is less than 18 mcg/dL (496 nmol per liter).

If you suspect or confirm adrenal insufficiency, give hydrocortisone 2 mg per kilogram IV bolus (maximum dose of 100 mg).

Therapeutic endpoints

Titrate vasoactive agents and septic shock to therapeutic endpoints, including

  • good distal pulses and perfusion
  • adequate blood pressure
  • SCV 02 greater than or equal to 70%
  • correcting metabolic acidosis and lactate concentration

Strict adherence to endpoints is recommended to avoid excessive vasoconstriction in key organs.

Norepinephrine (p 227)

Classification: Inotrope, vasopressor, catecholamine

Indications: Hypotensive shock (ie associated with low SVR unresponsive to bolus fluid administration.

Dosage and Administration:

Hypotensive Shock
IV/IO                                                                       0.1 to 2 mcg/kg per minute infusion                                                                                       (titrate to desired change in blood                                                                                           pressure and systemic perfusion)

Actions:

  • Activates alpha-adrenergic receptors (increased smooth muscle tone)
  • Activates myocardial beta1-adrenergic receptors (increased contractility and heart rate); the heart rate effect is blunted by baroreceptor stimulation that results from the vasocontrictive effect.

Distribution: Extracellular space

Metabolism: Liver, kidney, sympathetic nerves

Excretion: Urine

Half-life: 2 to 4 minutes

Pharmacodynamics

(IV/IO):

  • Onset–< 30 Minutes
  • Peak–5 to 10 minutes
  • Duration–< or = 10 minutes after stopping infusion

Monitoring: Monitor ECG continuously and blood pressure frequently

Adverse Effects:

  • CNS–Headache, anxiety
  • Resp–Respiratory distress
  • CV–Hypertension, tachycardia, bradycardia, arrhythmias
  • GU–Renal failure
  • Skin–Local necrosis (infiltration)

Precautions:

  • May produce hypertension, organ ischemia, or arrythmias.
  • Tissue infiltration may produce severe ischemia and necrosis. Infiltration with phentolamine may reduce local toxic effect of norepinephrine.
  • Do not mix with sodium bicarbonate.

Special Considerations:

  • Ideally should be administered via a central

 Dopamine (p 212)

classification: catecholamine, vasopressor, inotropic

Indications:

  • ventricular dysfunction, including cardiogenic shock
  • distributive shock

Available forms:

  • injection: 40, 80, 160 mg/mL
  • pre-deluded in D5 W: 0.8, 1.6, 3.2 mg/mL

Dosage and administration:

               Cardiogenic Shock, Distributive shock
IV/IO                                                                 2 to 20 µg per kilogram per                                                                                          minute infusion (titrate to                                                                                            desired response)

Actions:

  • Stimulates alpha adrenergic receptors (> 15 µg per kilogram per minute)                               — Increases SVR dear constriction of arterioles
  • Stimulates beta-1 adrenergic receptors (5 to 15 µg per kilogram per minute)                             — Increases heart rate (sinoatrial node effect)                                                                       — Increases myocardial contractility, automaticity, and conduction                               velocity (ventricular effect)
  • Stimulates beta 2 adrenergic receptors (5 to 15 µg per kilogram per minute)                              –Increases heart rate                                                                                                                   — Decreases SVR

Pharmacokinetics:

  • Absorption– (Not applicable with IV/IO route of administration)
  • Distribution– Extracellular space
  • Metabolism– Liver, kidney, plasma
  • Excretion– Urine
  • Half-life– 2 min.

Pharmacodynamics:

IV/IO

  • Onset– 1 to 2 min.
  • Peak– 10 min.
  • Duration–< 10 min. after infusion is stopped

Monitoring: Monitor ECG continuously and blood pressure frequently.

Adverse Effects:

  • CNS– Headache
  • Respiratory– Dyspnea
  • CV– Palpitations, premature ventricular contractions, SVT, VT, hypertension, peripheral vasoconstriction
  • G.I.– Nausea, vomiting, diarrhea
  • GU– Acute renal failure
  • Skin– Local necrosis (with infiltration), gangrene

Precautions

  • hi infusion rates (greater than 20 µg per kilogram per minute) produce peripheral, renal, and splanchnic vasoconstriction and ischemia; if infusion dose is greater than 20 µg per kilogram per minute is required, consider a addition of alternative adrenergic agent (e.g., epinephrine/norepinephrine).
  • Do not mix with sodium bicarbonate.
  • Tissue ischemia and necrosis may result if IV infiltration occurs. Infiltration with phentolamine may reduce local toxic effect of dopamine.

Special Considerations:

  • Central venous administration is preferred.
  • Inactivated in alkaline solutions.

Epinephrine (pp 213 + 214)

Classification: catecholamine, vasopressor, inotrope

Indications:

  • Anaphylaxis
  • Asthma (when more selective beta-2 agonists are not available)
  • Bradycardia (symptomatic)
  • Croup (nebulized)
  • Cardiac arrest
  • Shock
  • Toxins/overdose (e.g., beta-adrenergic blocker, calcium channel blocker)

Available Forms:

  • Injection: 1:1000* aqueous(1 mg/mL), 1:10,000 aqueous (0.1 mg/mL)                      Note: *on this page 1:1000 dilution is bold to differentiate this dilution from the standard 1:10,000 dilution.
  • IM autoinjector: 0.15 mg, 0.3 mg
  • Racemic solution: 2.25%

[On page 213 of the manual there are detailed dosing instructions for anaphylaxis, asthma, bradycardia (symptomatic), croup, cardiac arrest, toxins/overdose (e.g., beta-adrenergic blocker, calcium channel blocker). However in this post, I’m only giving the dose for treatment of shock.

Shock

IV/IO infusion–0.1 to 1 µg per kilogram per minute infusion (consider higher doses it needed)

Actions:

  • Alpha adrenergic receptor stimulation is dose and age-dependent.
  • Stimulates beta-1 adrenergic receptors
    • Increases heart rate, myocardial contractility, automaticity, and conduction velocity
  • Stimulates beta-2 adrenergic receptors (predominance of lower doses will be patient specific)
    • Increases heart rate and
    • Causes bronchodilation
    • Causes dilatation of arterioles (decreases diastolic blood pressure)

Pharmacokinetics:

  • Absorption– IM absorption is affected by perfusion (not applicable with IV/IO route of administration)
  • Distribution– Unknown
  • Metabolism– Liver, kidney, endothelium
  • Excretion– Unknown
  • Half-life– 2 to 4 min.

Pharmacodynamics

IM IV/IO Inhalation
Onset 5 to 10 min. Immediate 1 min.
Peak Unknown Within 1 min. Unknown

Adverse Effects:

CNS Tremors, anxiety, insomnia, headache, dizziness, weakness, drowsiness, confusion, hallucinations, intracranial hemorrhage (from severe hypertension)
RESP Dyspnea
CV Arrhythmias (especially tachyarrhythmias, e.g., SVT and VT), palpitations, tachycardia, hypertension, ST segment elevation, post resuscitation myocardial dysfunction
GI Nausea, vomiting
GU Renal vascular ischemia
ENDO Hyperglycemia, post resuscitation hyper adrenergic state
ELECT Hypokalemia (beta-2 adrenergic stimulation causes intracellular potassium shift)
 MISC Gluconeogenesis response increases serum lactate independent of any change in organ perfusion, making interpretation of serum lactate as a marker of ischemia more difficult

Precautions:

  • High doses produce vasoconstriction and may compromise organ perfusion.
  • Low doses may increase cardiac output with redirection of blood flow to skeletal muscles, producing decreased renal and splanchnic blood flow.
  • Myocardial 02 requirements are increased (as the result of increased heart rate, myocardial contractility, and with higher doses increased SVR).
  • Tissue ischemia and necrosis may result if IV infiltration occurs. Infiltration within Ptolemy may reduce local toxic effect of epinephrine.
  • Central venous access is preferred for it ministration.
  • Catecholamines are inactivated in alkaline solutions.
  • Observe at least two hours after croup treatment for “rebound” (i.e., recurrences stridor).

Contraindications: Cocaine induced VT

Special Considerations: when given IM in anaphylaxis, best absorption occurs from injection in the side rather than the deltoid muscle. Subcutaneous administration is not recommended for treatment of anaphylaxis because absorption is delayed.

 

Resources

Pediatric Advanced Life Support Manual, 2011. American Heart Association.

Another Great YouTube Video from Dr. Mellick–Pediatric Pulse Dose Pressor Administrationblog post of Oct 2, 2014 on tomwademd.net

Pulse Dosing of Epinephrine or Phenylephrine for Hypotension, blog post of Sept 10, 2013 on tomwademd.net

Dr. Mellick’s Vid: Pulse Dose Epi–Intubating the Unstable Patient (Watch and Read!), blog post of Jan 10, 2014 on tomwademd.net

 

 

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