Management of pulmonary hypertension in the perioperative setting

• ¹Overview:

  • Step 1: thorough preoperative assessment which would include not only history, etiology, duration of pulmonary hypertensive disease but also a characterization of progression and acuity

  • Step 2: determination of any physiological causes of increased pulmonary vascular resistance that may be present in the perioperative time frame (these factors could include hypoxia, hypercarbia, excessive sympathetic tone, presence of endogenous/exogenous vasoconstrictors, or acidosis)

  •  Step 3: to minimize the likelihood of the development of the above factors (assuming they are not present), perioperative intervention to ensure appropriate acid-base balance, ventilation, temperature, oxygenation ultimately careful management of  anesthesia depth are critical

•  ¹Intraoperative Hemodynamic issues:

  •  Given the critical need to minimize interoperative exacerbation of pulmonary hypertension, there are several considerations to optimize the hemodynamic status in such a way to ensure appropriate pre-loads, afterload, rhythm, inotropism, and chronotropism.These methods have been described as follows¹:

    1. "Maintain high preload so as to match the increased afterload faced by the right ventricle (RV).

    2. Maintain high systemic afterload (approximated by systemic vascular resistance) because the right ventricle is unable to increase cardiac output to compensate for decreased systemic vascular resistance.  If the systemic vascular resistance decreases, a progressive cycle of hypotension, RV ischemia, decrease cardiac output, and progressive hypotension may occur.

    3. Avoid increases in pulmonary afterload (PVR) by correcting physiologic precipitants of PH.  Therapeutic measures to decrease PVR ...may be immediately required if RV function diminishes.

    4. Maintain high contractility to enable the RV to sustain cardiac output in the face of increased PVR.

    5. Avoid bradycardia."

• Pharmacological interventions:

  • ¹Pulmonary vasodilators:generally these agents work through either a cAMP or a cGMP system.

    • Activation of adenylyl cyclase leads to increase cyclic AMP which activates a cAMP-dependent protein kinase  which alters the phosphorylation state of myosin promoting vasorelaxation. This effect may be mediated by changing the phosphorylation state of myosin light chain kinase in a manner that inhibits phosphorylation of myosin light chains.

      • Drugs that increase cAMP include the beta-receptor agonists, such as isoproterenol (Isuprel) and epinephrine

    • ^2,3Modulation of cGMP ( nitrovasodilators including sodium nitroprusside sodium (Nipride), nitroglycerin) through affecting guanylyl cyclase activity; unknown mechanisms (hydralazine (Apresoline) which may work through affecting calcium channel activity)

    • ²Calcium channel blockers which affect myosin light chain kinase activity through altering intracellular calcium concentrations

    • ⁴Prostaglandins and prostacyclins (PGI₂)--cAMP-mediated 2nd messenger relaxation.

    • ¹Some vasodilators act by inhibiting the breakdown of cyclic nucleotides.  These drugs are phosphodiesterase inhibitors and include amrinone (Inocor), milrinone (Primacor) and enoximone.

    • ¹Limitations of intravenous vasodilators in managing pulmonary hypertension:

      • These drugs may cause cause systemic hypotension and induce a reflex sympathetic stimulation thus increasing pulmonary vasomotor tone (vasoconstriction) and therefore exacerbating pulmonary hypertension.

      • Systemic hypotension may decrease right ventricular contractility secondary to reduced coronary perfusion.  As noted earlier, in patients with pulmonary hypertension, the right ventricle may be especially sensitive to hypotension.

      • Some of the drugs noted above, calcium channel blockers especially, may directly reduce myocardial contractility by decreasing calcium entry.  Negative inotropic effects which worsen right ventricular function exacerbate the hemodynamic problem.

      • Hypoxemia may be increased with pulmonary vasorelaxation because of increased ventilation-perfusion mismatching (hypoxic pulmonary vasoconstriction, HPV.)

  • ¹Nitrovasodilators:

    • Nonspecific pulmonary vasodilators such as Na nitroprusside sodium (Nipride) or nitroglycerin will decrease pulmonary vascular resistance but also significantly decrease systemic vascular resistance inducing systemic hypotension, not desirable in pulmonary hypertension.  

    • Furthermore, ventilation-perfusion mismatching is increased which can result in a reduction of PaO₂ in the presence of ARDS, other lung diseases, pulmonary emboli, COPD, chronic obliterative  pulmonary hypertension as well as during one-lung anesthesia.

  • ¹Calcium channel blockers.  Many calcium channel blockers cause pulmonary vasodilation.

    • Nifedipine (Procardia, Adalat) and nicardipine (Cardene) are more effective compared to diltiazem (Cardiazem) or verapamil (Isoptin, Calan) in this regard.

    • Calcium channel blockers will also inhibit hypoxic pulmonary vasoconstriction (HPV) and thus can decrease PaO₂ under some circumstances

  • ¹Prostaglandins:

    • Prostacyclin which is released from endothelial cells is an effective vasodilator (cAMP mechanism)

    • Intravenous prostacyclin (epoprostenol (Flolan)) is considered a  major therapeutic events in management of primary pulmonary hypertension and may also be effective in patients with secondary PH.

    • Epoprostenol (Flolan) promotes long-term benefit in pulmonary hemodynamics with reduced pulmonary vascular resistance and pulmonary artery pressure.

      • Intravenous infusion: prostacyclin half-life = about 2-3 minutes; it is classified as a non-selective pulmonary vasodilator with pulmonary and systemic vasodilation.

      • Aerosol delivery allows prostacyclin to function as a selective pulmonary vasodilator in patients with ARDS as well as in newborns with congenital heart disease.  In this setting, PaO₂ generally improves.

      • Limited toxicity associated with inhaled prostacyclin may result in this treatment becoming an alternative toinhaled nitric oxide

  • ¹Inhaled nitric oxide:a selective pulmonary vasodilator which reduces pulmonary vascular tone.

    • Causes smooth muscle relaxation with minimal systemic effects because nitric oxide will be inactivated in the pulmonary circulation (following rapid binding to hemoglobin and ultimately oxidized to methemoglobin.

    • Hypoxic pulmonary vasoconstrictive state is generally unaltered since inhaled nitric oxide is distributed only to those alveoli which are functional.  This is an advantage of the aerosol route  of administration.

  • ¹Intravenous adenosine (Adenocard): Pulmonary adenosine (Adenocard) levels exceed systemic levels because of significant erythrocyte and pulmonary endothelial  adenosine metabolism.  With the use of appropriate dosage range, selective pulmonary vasodilation may be obtained.

• ⁵Recommended treatment approaches:

  • Start with acute drug testing with short-acting pulmonary vasodilators.Rationale-determining the extent of pulmonary vasodilator reserve and reactivity.

  • Appropriate agents: intravenous adenosine (Adenocard), inhaled nitric oxide, intravenous prostacyclin all appear to have similar effects in reducing pulmonary vascular resistance with limited systemic effects.

  • Dosages:

    • adenosine (Adenocard): constant infusion beginning at 50 ug/kg/minute dose  increasing every two minutes until side effects develop; maximal effectiveness is determined by highest tolerated dose.

    • prostacyclin: beginning dose 2 ng/kg/min increasing every 30 minutes until site effects develop.

    • nitric oxide: administered by inhalation -- initial dose 5-10 ppm (parts per million) increasing every few minutes until no further improvement is noted