143R. Chawla and S. Todi (eds.), ICU Protocols: A stepwise approach, DOI 10.1007/978-81-322-0535-7_18, © Springer India 2012

A 55-year-old male patient presented with acute respiratory distress. His heart rate was 140/min, BP was 70/40 mmHg, and respiratory rate was 34 breaths/min. Core temperature was 34.4°C. He was oliguric, and the abdomen was tender, fi rm, and distended. He was intubated and mechanically ventilated. A central venous catheter was inserted, and the central venous pressure (CVP) was 18 mmHg. He remained tachycardic and hypotensive.

J. V. Divatia , M.D., F.I.S.C.C.M. (*) Department of Anaesthesiology, Critical Care and Pain , Tata Memorial Hospital , Mumbai , India e-mail: jdivatia@yahoo.com

P. A. Khan , M.D. Department of Anaesthesiology, Critical Care and Pain , Tata Memorial Hospital , Mumbai , India

18 Fluid Therapy, Vasopressors, and Inotropes

Jigeeshu V. Divatia and Parvez Ali Khan

Fluids (crystalloid or colloid), vasopressors, and inotropes are common interventions in managing unstable patients in the ICU. These interventions should be used judi-ciously to maintain perfusion to vital organs while de fi nitive therapy is being insti-tuted. On the other hand, if they are used injudiciously, these interventions may be potentially harmful.

Step 1: Start fl uids for resuscitation In patients with new-onset hypotension, tachycardia, unexplained oliguria, or • other evidence of hypoperfusion such as increased lactate or base de fi cit, consider a fl uid challenge, if this seems to be of low risk clinically, for example, patients with no evidence of overt heart failure. Administer 500–1,000 mL crystalloid or 250–500 mL colloid over 30 min. In • patients with sepsis, crystalloids are the preferred initial resuscitation fl uid.

144 J.V. Divatia and P.A. Khan

Fluid challenge in the ICU should be protocolized with clear direction about the • various components of fl uid challenge—type of fl uid, rate of administration, clinical and pressure end points, and safety limits (see Chap. 16 ). Target CVP should be 8–12 mmHg in spontaneously breathing patients and • 12–15 mmHg in mechanical ventilated patients or those with preexisting decreased ventricular compliance, for example, in hypertensives. These parameters need to be individualized depending on patients’ clinical • status, comorbidity, and underlying pathology. Careful monitoring of patients clinically and hemodynamically is mandatory • during fl uid challenge to assess response as well as evidence of fl uid overload.

Step 2: Select fl uid for resuscitation There is no ideal fl uid for resuscitation. Outcomes are similar using either 0.9% • normal saline (crystalloid) or 4% albumin (colloid) for fl uid resuscitation. However, hemodynamic goals tend to be achieved faster with colloid resuscitation. Crystalloids are cheaper but infusion of large volumes of normal saline can cause • hyperchloremic acidosis, while colloids may cause coagulopathy, renal dysfunc-tion and anaphylactoid reactions. The total volume of HES 130/0.4 should be restricted to 50 mL/Kg/day. The • older generation of starches (HES 200/0.5) should be avoided, as they have been shown to be associated with higher incidence of renal failure and coagulopathy, and if at all used, the volume should be restricted to 33 mL/Kg/day. The new generation of starches (HES 130/0.4) appear to have a lower incidence of coagulopathy. All hyperoncotic colloids (including 10% HES and 20% albumin) can precipi-• tate renal dysfunction. They should always be combined with crystalloids. Most synthetic colloids are prepared in solution with normal saline. Hence, large • volumes of such colloids can also cause hyperchloremic acidosis with resultant coagulopathy. Crystalloids (lactated Ringer’s solution) and colloids in balanced solution do not • cause hyperchloremic acidosis and may be preferable to normal saline for large volume resuscitation.

Step 3: Assess response Response to a fl uid challenge should be assessed clinically by features of • increased perfusion like improved sensorium, increased sense of well-being, and increased urine output. This should also be assessed by improvement of hemodynamic parameters such • as decreased tachycardia, improved blood pressure, and improved CVP or wedge pressure. Increasingly, it has been realized that static measures of preload such as CVP or • pulmonary artery occlusion pressure (PAOP) do not adequately re fl ect need for fl uid challenges. There are two principal reasons for this realization:

As per Frank–Starling law, preload (CVP or PAOP) is related to stroke volume –or cardiac output in a curvilinear manner; that is, rise in preload will result in

14518 Fluid Therapy, Vasopressors, and Inotropes

increasing stroke volume in the steep part of the curve till the fl at part is reached when increasing preload will not lead to further increase in stroke volume. In a given patient, it is dif fi cult to predict the position of a preload measure on this curve by static values as it is dependent on ventricular com-pliance which is variable. Left ventricular compliance varies among patients and may vary at different –times in the same patient, so the pressure–volume curves are variable; thus, a stiff ventricle (hypertrophy) will lead to a decrease in ventricular compliance with shift of pressure–volume curves of the ventricle to the left. It means high pressure values (CVP or PAOP) for the same or low ventricular volume and a more compliant (dilated) ventricle will shift this curve to the right; thus, a low pressure (CVP or PAOP) reading may indicate a high ventricular volume. Thus, it is dif fi cult to predict ventricular volume by a given pressure index (CVP or PAOP).

Dynamic indices such as pulse pressure variation (PPV), systolic pressure variation • (SPV) or stroke volume variation (SVV), echocardiographic vena cava diameter, or esophageal Doppler aortic blood fl ow changes during controlled positive-pressure ventilation or during passive leg raising in spontaneously breathing patients are more representative for predicting fl uid responsiveness (see Chap. 16 ). When the risk of fl uid challenge is not trivial, for example, in patients with com-• promised lung or cardiac function, consider using a dynamic predictor to guide fl uid boluses. Since the hemodynamic state changes rapidly, reassessment of hemodynamics • should be done frequently.

Step 4: Select inotrope or vasopressors Despite adequate volume replacement, if the patient is hypotensive and perfusion • of vital organs is jeopardized, vasoactive agents may be administered to improve cardiac output and blood pressure. It is useful to understand the receptors through which adrenergic agents exert • their effect. Three broad groups of agents may be identi fi ed:• 1. Predominant b -agonists (dobutamine, dopexamine, isoprenaline) 2. Predominant a -agonists (phenylephrine) 3. Those with mixed b - and a -effects (adrenaline and noradrenaline). In general, when the heart is failing, and the peripheral vascular resistance is • normal, an agent with predominant inotropic effect (especially a b -1 selective agent) would be a good choice. If there is vasodilatation, a vasoconstrictor with predominant • a -agonist activity is appropriate. Familiarize with doses and effects of commonly used inotropes and vasopressors. • Consider practical aspects of vasopressor infusion:•

Infuse through large veins preferably central veins. – Use multi-lumen catheters and use dedicated lumen for vasopressor infusion. – No other drug bolus or infusion should be given through the same lumen. –

146 J.V. Divatia and P.A. Khan

Use infusion or syringe pumps or other infusion controllers. – Invasive arterial pressure should be measured. – Dobutamine and other inodilators may be given through peripheral line. –

Volume de fi cit should always be corrected as much as possible before resorting • to vasopressors which would lead to a false sense of security by increasing blood pressure while underlying hypovolemia and resultant low perfusion will lead to subsequent organ dysfunction.

Step 5: Titrate inotropes and vasopressors All inotropes and vasopressors should be titrated so that tissue perfusion is • restored with the lowest dose of drug and to the desired end points with minimal or no side effects:

Titrate to clinical improvements in heart rate (HR) and mean arterial pressure –(MAP). Titrate inotropes to desired cardiac output. –

Do not aim for supranormal cardiac output:• Titrate vasopressors to MAP of 65–70 mmHg. – In patients with long-standing hypertension, renal failure, recent cerebral –infarct, and increased intra-abdominal pressure, a higher MAP may be desirable. In trauma with active bleeding, a lower MAP till bleeding source is controlled –is advisable. Aiming for higher MAP than desired may result in unnecessary vaso- –constriction. Titrate to achieve adequacy of organ perfusion –

Urine output more than 0.5 mL/Kg/h • ScvO •

2 more than 70%

Reduction in lactate levels over time (e.g., 20% over 2 h) • Watch for side effects: tachycardia, arrhythmias, cardiac ischemia. •

Step 6: Customize use of inotropes and vasopressors (Tables 18.1 and 18.2 ) Choice of inotropes and vasopressors may vary depending on clinical situation. • • Levosimendan

Table 18.1 Agents used in myocardial infarction and cardiogenic shock

Clinical picture Low cardiac index (CI) but systolic blood pressure (SBP) > 100 mmHg, high left ventricular (LV) fi lling pressures

Low CI < 2.2 L/min/M 2 , SBP < 90 mmHg, high LV fi lling pressures

Low CI < 2.2 L/min/M 2 , SBP < 90 mmHg, high right atrium and right ventricular diastolic pressures

Choice of inotropic agents

Dobutamine/milrinone Dopamine/noradrenaline/intra-aortic balloon pump (IABP)

Volume replacement/dobutamine and noradrenaline/IABP

14718 Fluid Therapy, Vasopressors, and Inotropes

Table 18.2 Doses and effects of commonly used inotropes and vasopressors

Drug Dose/range ( m g/Kg/min)

Predominant receptor Effects

Adrenaline 0.01–0.02 b -2 Lowered systemic vascular resistance (SVR), BP

0.03–0.20 b -1 Increased contractility, HR, cardiac output (CO), lactic acidosis, hyperglycemia

0.20–0.30 A lpha Increased SVR, BP, impaired splanchnic perfusion

Noradrenaline 0.01–0.40 a -1, a -2, b -2 Raised SVR, BP, possible re fl ex fall in HR, possible fall in CO In fl uid-resuscitated patients, improved renal and splanchnic blood fl ow

Dopamine 0.01–3.00 Dopaminergic Renal and splanchnic Vasodilatation

3.0–7.0 b -1 Increased contractility, HR, CO

>7.0 A lpha 1 Increased SVR, BP, variable effects on splanchnic circulation and gastric mucosal fl ow

Dobutamine 3.0–20.0 b -1 (plus some b -2, a )

Increased contractility, decreased SVR, increased CO, increased HR

Dopexamine 0.5–6.0 b -2 (plus some b -1, a and dopaminergic)

Increased contractility, decreased SVR, increased CO, increased HR, increased renal and splanchnic blood fl ow at low dose

Isoprenaline 0.01–0.03 b -1, b -2 Decreased SVR, increased HR

Milrinone bolus 50 m g/Kg Increased cAMP, increased contractility, coronary blood fl ow

0.35–0.75 Decreased SVR, PVR, arrhythmias Phenylephrine 0.1–3.0 A lpha 1 Prolonged action potential,

Increased SVR, inotropy Levosimendan 6–12 m g/Kg

loading dose over 10 min followed by 0.05–0.2 m g/Kg/min as a continuous infusion

Calcium sensitizer

Increased sensitivity of actinomy-cin to calcium. Increased myocar-dial contractility.

It is a myo fi lament calcium sensitizer. It increases myocardial contractility –without increasing myocardial ATP consumption, thereby improving contrac-tion at low energy cost. It causes normal or improved diastolic relaxation and vasodilatation. – It has been studied in acute decompensated heart failure, during and after –cardiac surgery, and postmyocardial infarction.

148 J.V. Divatia and P.A. Khan

• Digitalis glycosides The digitalis glycosides have long been used as inotropic agents. – However, today their role in the treatment of acute heart failure or cardiogenic –shock is limited to control of the ventricular rate response in fast atrial fi brillation. The onset of action of effects of digoxin takes 90 min after an intravenous –loading dose, and peak effect occurs at 2–6 h. The effects of digoxin are modest and unpredictable, and it has a narrow – therapeutic index.

• Agents used in septic shock The Surviving Sepsis Campaign makes the following evidence-based recom-mendations in patients with sepsis:

– Vasopressors Recommend to maintain MAP • ³ 65 mmHg. Recommend noradrenaline centrally administered as the initial vaso-• pressors of choice. Suggest that dopamine, adrenaline, phenylephrine, or vasopressin should • not be administered as the initial vasopressor in septic shock. Vasopressin at dose of 0.03 unit/min may be subsequently added to nora-• drenaline with anticipation of an effect equivalent to noradrenaline alone. Use adrenaline as the fi rst alternative agent in septic shock when blood • pressure is poorly responsive to noradrenaline Recommend not to use low-dose dopamine for renal protection. • Recommend to insert an arterial catheter in patients requiring vaso pressors, • as soon as practical.

– Inotropic therapy Recommend the use of dobutamine in patients with myocardial dysfunction • as supported by elevated cardiac fi lling pressures and low cardiac output. Do not increase cardiac index to predetermined supranormal levels. •

Step 7: Understand limitations of vasopressor and inotrope therapy All inotropic and vasopressor drugs may increase myocardial oxygen demand. • Increasing blood pressure by use of vasopressors does not lead to increased • perfusion all the time; in certain circumstances like hypovolemia, it might lead to decreased fl ow to end organs. Tachycardia may occur, especially in volume-depleted patients. • Arrhythmias. • Catecholamines also have signi fi cant neurohumoral and metabolic effects, which • might be deleterious, for example, hyperglycemia and hyperlactatemia induced by adrenaline and suppression of prolactin by dopamine.

Step 8: Wean inotropes and vasopressors All attempts should be made to treat underlying cause of low perfusion state • whenever feasible and vasopressors should be weaned off at the earliest. If necessary, additional fl uid challenges may be used judiciously in order to wean • off vasopressors.

14918 Fluid Therapy, Vasopressors, and Inotropes

Suggested Reading

1. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362:779–89.

The use of dopamine was associated with a greater number of adverse events. There were more arrhythmic events among the patients treated with dopamine than among those treated with norepinephrine. A subgroup analysis showed that dopamine, as compared with norepinephrine, was associated with an increased rate of death at 28 days among the 280 patients with cardio-genic shock.

2. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008;34:17–60.

Widely practiced guideline, a must read for all intensivists 3. Antonelli M, Levy M, Andrews PJF, et al. Hemodynamic monitoring in shock and implications

for management International Consensus Conference, Paris, France; 2006 Apr 27–28. Intensive Care Med. 2007;33:575–90.

Consensus conference statements. 4. Beale RJ, Hollenberg SM, Vincent JL, Parrillo JE. Vasopressor and inotropic support in septic

shock: an evidence-based review. Crit Care Med. 2004;32(Suppl):S455–65. A comprehensive literature review on the subject

Websites

1. www.survivingsepsis.org Homepage of surviving sepsis campaign 2. www.slideshare.net Powerpoint slide collection on the topic