Dr Nick Taylor Visiting Emergency Specialist Teaching Hospital Karapitiya

Dr Nick Taylor Visiting Emergency Specialist Teaching Hospital Karapitiya Senior Specialist and Director ED Training Clinical Lecturer, Australian National University Canberra Hospital, Australia

Inotropes increase myocardial contractility Vasopressors increase vascular tone

BP = CO X SVR CO = SV x HR Pressure does not equal flow No such thing as normal blood pressure perfusion and end organ function are what matters

Myocyte stretch Changes in venous return Changes in plasma volume Contractility Sympathetic tone Circulating catecholamines Exogenous inotropes Heart rate Sympathetic and parasympathetic tone Circulating catecholamines Exogenous drugs with chronotropic effects

Endogenous catecholamine with strong α1 agonist activity and modest β1 activity, Strong vasoconstriction and less potent inotropy. Net increase in systolic blood pressure (SBP), diastolic blood pressure, and pulse pressure, Minimal effect on cardiac output Reflex bradycardia from vasoconstriction balances mild chronotropic effects

Endogenous catecholamine with high affinity for α1, β1, and β2 receptors Causes vasoconstriction, positive inotropy, and bronchodilation. At high infusion rates the diastolic time is increased and myocytes release local vasodilators leading to increased coronary blood flow Associated with: potent metabolic effects lactic acidosis, hyperglycaemia decreased mesenteric, coronary, and renal conductance reduced renal blood flow

Synthetic catecholamine that binds β1 and, to a lesser extent, α1 and β2 receptors. This results in strong inotropic and weaker chronotropic activity. A mild reduction in SVR is a reflex to increased inotropy. Dobutamine s activation of α1 and β2 receptors is of questionable clinical significance. Increases myocardial oxygen consumption (useful in pharmacologic cardiac stress testing) and is potentially harmful to patients at-risk for cardiac ischemia. Significant pharmacologic tolerance can develop after only 72 hours. Safe to administer by peripheral IV but can induce ventricular arrhythmias at any dose.

Central neurotransmitter and immediate precursor to nor adrenaline Traditionally, systemic effects are considered dose-dependent. At low infusion rates (0.5 3 mg/kg/min), stimulation of D1 postsynaptic receptors in coronary, renal, mesenteric, and cerebral vascular beds, and D2 presynaptic receptors in renal tissue, result in mild vasodilation and diuresis. The clinical significance of this renal dose of dopamine is unclear. In critically ill patients, low-dose dopamine infusions have been shown not to increase GFR or protect against ARF

The increase in splanchnic blood flow and does not alter other measures of mesenteric perfusion. Intermediate doses of dopamine (3 10 mg/kg/min) activate β1 receptors and increase endogenous norad release, increasing cardiac inotropy and SVR. High doses (10 20 mg/kg/min), α1 activity predominates resulting in vasoconstriction and increased SVR. It should be noted that these distinctions are derived generally and in clinical practice the response is patient-specific.

Vasopressin, or ADH, is an endogenous hormone stored in the posterior pituitary gland and released in response to increased plasma osmolality, hypotension, pain, nausea, and hypoxia. It is also synthesized by the heart in response to cardiac wall stress, and by the adrenal glands in response to increased catecholamine secretion. It acts on V1 receptors in vascular smooth muscle to induce vaso- constriction, and V2 receptors in the renal collecting tubules to increase collecting duct permeability and renal water reabsorption.

Vasopressin increases SVR but reflex increases in systemic vagal tone result in a minimal net effect on cardiac output. Vascular sensitivity to noradrenaline is increased when vasopressin is coadministered, creating a synergistic effect and decreasing the dose (and side effects) of noradrenaline. It may be useful in sepsis because its vasoconstrictive effects are preserved in hypoxic and acidotic conditions.

Direct effect on vascular α 1 receptors much greater than β Indirect mechanism of action related to the stimulation of noradrenaline release Useful as bolus dose for temporizing or counteracting anaesthetic drugs Reflex Bradycardia

Acts on β 1 receptors and is primarily chronotropic with mild inotropic actions β 2 receptor mediated vasodilation causes a decrease in MAP Proarrhythmic

DRUG ACTION DOSE SIDE EFFECTS Noradrenaline α1> β1 0.01-0.5 µg/kg/min Tachyarrhythmia, inc myocardial O2 demand Adrenaline α1, β1, β2 0.01-0.75 µg/kg/min Tachyarrhythmia, inc myocardial O2 demand, Lactic acidosis Dobutamine β1> β2 2-20 µg/kg/min Tachyarrhythmia, inc myocardial O2 demand, tolerance Dopamine α1, β1, dopa1 0.5-25 µg/kg/min Tachyarrhythmia, inc myocardial O2 demand Vasopressin α1,v1, V2, V3 0.04 U/min GI hypoperfusion Metaraminol α1>>β1 0.5-1mg Reflex bradycardia Isoprenaline β1>> β2 0.5-10 µg/kg/min Tachyarrhythmia, inc myocardial O2 demand

55F Cardiogenic shock Presents on Norad 2mcg/kg/min, Adrenaline 1mcg/kg/min, dobutamine 20mcg/kg/min, dopamine 24 mcg/kg/min BP 71/34 Dopa/Dobuta Stopped Adr at 0.5, NA at 0.2: BP 105/45

Start at a moderate dose and titrate down when patient is severely hypotensive Remember the lowest dose for your target/end point is what is needed do NOT set and forget In general use no more than 2 agents In general a moderate dose of two is better than a max dose of one and a minimal dose of another Wean the drug with the most side effects first tachycardia will not help diastolic fill time All inotropes/pressors have adverse consequences your job is to optimise the benefit to harm ratio

A 46 yo male comes in with 3 days of fever and flank pain. T 105, P 121, BP 75/45 Urine: Nitrate++, WCC ++ He does not improve after 2.5L IV crystalloid What is the diagnosis?

NORADRENALINE (Strong) Rationale: Norad, adrenaline, dopamine and vasopressin can all increase blood pressure in patients with septic shock. The 2012 Surviving Sepsis Guidelines suggest using norepinephrine as the first line agent for these patients.(change from Norad or Dopamine)

Two recent large RCTs comparing mortality in patients with shock who were treated with dopamine or norad. One of the RCTs included only patients with septic shock, while the other included patients with all types of shock. The RCT with only septic shock patients demonstrated a mortality benefit in favor of norad. Multiple observational studies demonstrated higher mortality in patients with septic shock who were treated with dopamine. With respect to morbidity, the use of dopamine has been associated with an increased risk of dysrhythmias. There are two recent systematic reviews and a meta-analysis that compare dopamine to norad. Two of the three concluded that norad confers a mortality benefit. All three demonstrated an increased risk of cardiac dysrhythmias when dopamine is used. Vasu TS, Cavallazzi R, Hirani A, et al. Norepinephrine or Dopamine for Septic Shock: Systematic Review of Randomized Clinical Trials. J Intensive Care Med 2012;27: 172-178. De Backer D, Aldecoa C, Nijmi H, et al. Dopamine versus norepinephrine in the treatment of septic shock: A metaanalysis. Crit Care Med 2012;40(3):725-30. Xu B, Oziemski P. Dopamine versus noradrenaline in septic shock. Australasian Med J 2011;4(10):571-4.

Initially titrate to an MAP of 65-70. This target has been shown to provide adequate end organ perfusion and no mortality benefit has been seen with higher MAP targets. Higher MAP (75-85) is associated with fewer patients getting ARF (32% vs 42%)in those with atherosclerosis or HTN at the expense of doubling AF rate and spending longer on vasoactive agents. MAP targets must always be individualized and based on clinically relevant perfusion markers, such as urine output, mental status, skin perfusion, and serum lactate clearance. Initial vasopressor treatment should be concomitant with volume expansion Pierre Asfar et al. High versus Low Blood-Pressure Target in Patients with Septic Shock. N Engl J Med March 18, 2014; DOI: 10.1056/NEJMoa1312173

After starting norad and titrating to 1mcg/kg/min, the patient has a BP of 84/32, UO is poor and he is still poorly perfused peripherally You decide to do a bedside echo A bedside echo shows acute LV hypokinesis

Previous studies demonstrated that dobutamine improved cardiac index as well as creatinine clearance and gastric microcirculation. More recent studies on the use of dobutamine in septic shock also demonstrated an improvement in cardiovascular parameters, but only limited improvement in microcirculation. Dobutamine is recommended in the 2012 Surviving Sepsis Guidelines for patients who demonstrate low cardiac output despite volume resuscitation.

The 2012 Surviving Sepsis Guidelines recommend the addition of adrenaline to noradrenaline when [an] additional agent is needed to maintain adequate blood pressure. Mahmoud et al compared dobutamine to adrenaline for cardiovascular support in patients with septic shock who were already being treated with norad. This study did not show a difference in mortality between the groups. Serum lactate levels and ph were worse in the adrenaline group. Mahmoud K, Ammar A. Norepinephrine supplemented with dobutamine or epinephrine for the cardiovascular support of patients with septic shock. Indian J of Crit Care Med 2012;16(2):75-80. Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: A randomised trial. Lancet 2007;370(9588):676-84.

The patient does not seem to be improving with catecholamine therapy Your consultant asks you to start Vasopressin

UNCERTAIN. Some patients with septic shock are vasopressin deficient but the clinical importance of this is unknown. When compared to norad as a first line agent for septic shock, vasopressin did not achieve MAP targets and rescue norad was required. Vasopressin has been shown to reduce the dose of catecholamines required to achieve MAP targets in patients with septic shock The VASST study did not demonstrate a survival benefit when a vasopressin infusion was added to patients with septic shock who were already being treated with at least 5 mcg/min of norepinephrine. Subgroup analysis of this study suggested that patients who were on lower doses of norad when vasopressin was initiated might have better survival. 2 subsequent studies suggest a lower mortality when VP is added to low dose Norad

A 61 yo female presents with LAD STEMI, BP of 70/45 and acute pulmonary oedema Bedside echo reveals septal hypokinesis What is the diagnosis?

Guidelines suggest aiming for MAP of 65-70, as evidence does not support benefit when higher targets are achieved

There exists no clear evidence-based recommendation for choice of agents in the setting of cardiogenic shock. The best strategy seems to be noradrenaline if hypotension is severe (SBP <70), or dobutamine if hypotension is moderate (SBP 70 100)

A large, high-quality, multicenter, randomized trial compared noradrenaline to dopamine as first-line vasopressor therapy for patients presenting in shock. No difference in mortality was found between groups overall Subgroup analysis of cardiogenic shock demonstrated that use of dopamine was associated with a significantly higher 28-day mortality. A Cochrane review suggested that this may have been due to chance There was also a higher incidence of arrhythmia in the dopamine group overall. Other evidence supports the concept that dopamine may be a sub-optimal choice of vasopressor in cardiogenic shock. An analysis of a large, multicenter prospective observational cohort study suggests that dopamine use may be associated with a higher mortality in shock of all etiologies. This further supports the evidence in favour of norepinephrine. De Backer D, Biston P, Devriendt J, et al. Comparison of Dopamine and Norepinephrine in the Treatment of Shock. NEJM 2010;362:779-89. Sakr Y, Reinhart K, Vincent JL, et al. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med 2006;34:589-97.

Your consultant asks you to change the Norad to Dobutamine Is there any evidence for this?

Inotropes are a double edged sword in cardiogenic shock Evidence is not available to definitively answer the question Watch for evidence of further ischaemia Guidelines recommending use are not evidenced based but dobutamine is in common practice No difference bewteen dobutamine + NAdr vs Adr only - except Adr causes lactic acidosis Current recommendations are for dobutamine in decompensated LVF with evidence of poor peripheral perfusion or post AMI shock with BP 70-100 Use lowest dose to achieve target MAP

An 18 yo F presents with facial swelling, wheeze and stridor after eating seafood BP is 80/30 First dose of IM Adrenaline is not helping

Adrenaline is the drug of choice Repeat IM bolus into gluteus Low concentration infusions are easy to make up (0.5mg in 500ml N/Saline) Run at 1ml/kg/hr and increase as needed Methylene blue 1.5mg/kg can be tried for adrenaline resistant anaphylaxis

A 51 yo M presents with P 96 and BP 69/35 The cause of shock is unclear

Evidence from 2 large studies suggests Noradrenaline should be first line due to lower arrhythmogenicity c.f. Dopamine and lower metabolic side effects c.f. Adrenaline De Backer D, Biston P, Devriendt J, et al. Comparison of Dopamine and Norepinephrine in the Treatment of Shock. NEJM 2010;362:779-89. Myburgh JA, Higgins A, Jovanovska A, et al. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008;34(12):2226-34.

A 75 yo man is in a ventricular escape rhythm with a BP of 78/45 Someone is going to get a pacing defibrillator so you can externally pace him What drug should you start in the meantime?

Adrenaline is the drug of choice in this circumstance. It has positive chrono/inotropic effects Isoprenaline has now been removed from guidelines as first line because it can worsen hypotension due to vasodilatation

No evidence to guide first choice in Neurogenic, obstructive or hypoadrenal shock Hypovolaemic shock should not routinely be given vasoactive drugs

Inotropes and Vasopressors can be safely delivered by Central, Peripheral or Intraosseous routes If peripheral IVs are used, they should be changed to central access after 4-6 hours and placed in large veins only IVs need to be checked first and you need a circulation obs protocol

Eighty-five articles with 270 patients met all inclusion criteria. A total of 325 separate local tissue injury and extravasation events were identified, with 318 events resulting from peripheral vasopressor administration and 7 events resulting from central administration. There were 204 local tissue injury events from peripheral administration of vasopressors, with an average duration of infusion of 55.9 hours (±68.1), median time of 24 hours, and range of 0.08 to 528 hours. In most of these events (174/204, 85.3%), the infusion site was located distal to the antecubital or popliteal fossae. CONCLUSIONS: Published data on tissue injury or extravasation from vasopressor administration via peripheral IVs are derived mainly from case reports. Further study is warranted to clarify the safety of vasopressor administration via peripheral IVs A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. Loubani OM1, Green RS2. Crit Care. 2015 Jun;30(3):653.e9-17. doi: 10.1016/j.jcrc.2015.01.014. Epub 2015 Jan 22.

Step I If the pt is relying on the agent for their hemodynamics, switch the pressor to another IV or place an immediate IO or central line. Step II Do not pull the cannula yet Step III Suck out as much as you can Step IV Administer subcutaneous phentolamine mesylate (Regitine) using 25 G or smaller needle Comes in 5 mg per 1 ml vials. Place in 9 ml of NS A dose of 0.1 to 0.2 mg/kg (up to a maximum of 10 mg) should then be injected through the catheter and subcutaneously around the site. Administered as soon as the extravasation is detected, even if the area initially looks just a little white or OK. Should see near immediate effects; otherwise consider additional dose. Now pull the catheter. May cause systemic hypotension (but they should be on pressors at another site) Step V Consult Plastics Source: http://emcrit.org/podcasts/peripheral-vasopressors-extravasation/

Evidence overall is weak Noradrenaline is first line in most situations Dopamine is proarrhythmogenic and probably leads to higher mortality Adrenaline is equivalent from a mortality perspective but leads to lactic acidosis and more tachycardia Low dose dobutamine is reasonable to add Peripheral access is OK for short term use

Emerg Med Clin N Am 32 (2014) 823 834 http://dx.doi.org/10.1016/j.emc.2014.07.006

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