Hypoxic pulmonary vasoconstriction & hypertensive crisis

1. Hypertensive crisis management in hypoxemic situations in ICU. Impact of hypoxic pulmonary vasoconstriction.

2. Hypoxic pulmonary vasoconstriction inhibition & hypertensive crisis management Case report: vasodilator-induced worsening of hypoxia. Inhibition of hypoxic pulmonary vasoconstriction (HPV). Underlying compensatory mechanisms in hypoxia: HPV Physiological role Efficiency A blation Mechanism Hypertensive crisis in hypoxia Understanding Management

3. 1. Vasodilator-induced worsening of hypoxia: Role of inhibition of hypoxic pulmonary vasoconstriction (HPV). 55-year old man with hypoxemic pneumonia initial traumatic cervical & thoracic vertebral fracture nosocomial Pseudomonas aeruginosa & Haemophilus influenzae infection (day 10) rapidly progressing ARDS ceftazidime/ ciprofloxacine , mechanical ventilation, inhaled NO, tracheotomy (day 18) favorable evolution FiO 2 45%; SpO 2 : 98%; PaO 2 =111 mmHg; PaCO 2 =41mmHg; pH=7.48 (day 20) hypertension > 180mmHg (day 20) probably associated with sympathetic hyperactivity (concomitant with awakening) treated with i.v. vasodilator: nicardipine i.v. 4mg/h worsening of hypoxia FiO 2 45%; SpO 2 : 92%; PaO 2 =60 mmHg; PaCO 2 =41mmHg ; pH=7.5 withdrawal of nicardipine favorable evolution with FiO2 80%: SpO2=100% Cotte J, et al. Rev Pneumol Clin (2012)

4. Inhaled Nitric Oxide in refractory hypoxemia in ARDS Inhaled Nitric Oxide: potent vasodilator delivered directly to ventilated areas to improve ventilation-perfusion mismatch results in improved oxygenation relieving pulmonary hypertension resulting from regional hypoxia. The current evidence: suggests that inhaled nitric oxide should not be routinely used in patients with ARDS may be considered as adjunctive therapy in selected patients ( eg , those with coexisting pulmonary hypertension) to transiently improve oxygenation in patients with severe ARDS while other therapies are considered. Pipeling M, et al. JAMA. 2010;304(22):2521-2527

5. Effects of systemic vasodilation (from intravenous, subcutaneous, or oral administration) versus selective pulmonary vasodilation (from inhalation). Siobal M, et al. Respir Care 2010;55(2):144 –157.

6. In contrast to iNO and inhaled prostacyclin (PGE1), intravenous prostacyclin caused systemic vasodilation , which worsened arterial oxygenation in ARDS. Siobal M, et al. Respir Care 2010;55(2):144 –157. PaO 2 with inhaled or infused prostacyclin or inhaled nitric oxide (INO) in 10 adult patients with acute respiratory distress syndrome.

7. Pulmonary vasodilator site of action in the endothelial and smooth-muscle cell . Siobal M, et al. Respir Care 2010;55(2):144 –157. iloprost ( Ventavis ) epoprostenol ( Flolan ) ambrisentan ( Volibris ) bosentan ( Tracleer ) alprostadil ( Prostin VR) sildenafil ( Revatio ) nitroglycerine nitroprusside

8. 2.1 Physiological role of Oxigen sensing and coordinating mechanisms Evolution in circulatory system: Branchial arteries in the Rainbow Trout constrict to hypoxia whereas systemic arteries dilate. Microvessels in frog’s skin, which in amphibians function like lungs, contract to hypoxia. Moudgil , et al. J Appl Physiol 98:390-403, 2005

9. 2.1a Physiological role of Hypoxic Pulmonary Vasoconstriction HPV: adaptive vasomotor response to alveolar hypoxia redistributes blood to optimally ventilated lung segments active process of vasoconstriction involving the small muscular “resistance” pulmonary arteries (PA ) Simultaneous systemic opposing response: hypoxia dilates most arteries decrease of systemic vascular resistance (e.g. renal vasodilation ) Moudgil , et al. J Appl Physiol 98:390-403, 2005

10. 2.1b Physiological role of Hypoxic Pulmonary Vasoconstriction Elicited by: moderate physiologically relevant hypoxia (e.g. summit of Mount Everest) Kinetics in response to hypoxia: onsets in minutes reaching a maximum within 15 min can be sustained for hours exposure for 3 h can elicit selective suppression of HPV (down-regulation) Moudgil , et al. J Appl Physiol 98:390-403, 2005

11. 2.1c Physiological role of Hypoxic Pulmonary Vasoconstriction Genetical adaptation to life in high altitude: The Yak and the native Tibetan have weak or absent HPV Moudgil , et al. J Appl Physiol 98:390-403, 2005 Picture: http://www.mantra-tibet.com

12. 2.1d Physiological regulation of HPV HPV is inhibited by: substance P calcitonine gene-related peptide atrial natriuretic peptides endothelium-derived vasodilators prostacylin nitric oxide (NO) alpha-adrenergic blockade beta-adrenergic stimulation increased left atrial pressure increased alveolar pressure alkalosis peripheral chemoreceptor stimulation Naeije R, et al. Critical Care 2001, 5:67–71

13. 2.2 The efficiency of Hypoxic Pulmonary Vasoconstriction Patients with ARDS are hypoxemic mainly because of an increased shunt : Altered gas exchange can be quantified by intrapulmonary shunt , expressed in percent of cardiac output. In ARDS, PaO 2 may increase by as much as 20 mmHg owing to vigorous HPV. Naeije R, et al . Critical Care 2001, 5:67–71

14. 2.2 The efficiency of Hypoxic Pulmonary Vasoconstriction Effects of HPV in lung disease characterized by shunt: HPV significantly improved PaO 2 at all shunt values. HPV improved SaO 2 when it was most decreased. Brimioulle S, et al . Appl Physiol 81:1535-1543, 1996.

15. 2.3a Ablation of Hypoxic Pulmonary Vasoconstriction Positron emission tomography measurements of regional blood flow : Pulmonary blood flow is redistributed upwards by hypoxic pulmonary vasoconstriction, and this is associated with preserved arterial PO 2 . Naeije R, et al . Critical Care 2001, 5:67–71 Experimental oleic acid lung injury when HPV is ablated by a minute amount of endotoxin . Intact hypoxic pulmonary vasoconstriction Ablated hypoxic pulmonary vasoconstriction

16. 2.3b Attenuation of Hypoxic Pulmonary Vasoconstriction Effect of nicardipine on regional HPV during experimental hypoxia: Left Lower Lobe ventilated with 100% nitrogen for 10 min dose-dependant attenuation of HPV reduction of systemic and pulmonary resistances augmentation of cardiac output neutral effect on blood-gas variables: no variation of PaO 2 & PaCO 2 augmentation of PvO 2 Nakazawa K et Amaha K. Br J Anaesth . 1988;60:547.

17. 2.3b Attenuation of Hypoxic Pulmonary Vasoconstriction Effect of nicardipine on regional HPV during experimental hypoxia: neutral on pulmonary resistances in normoxia dose-dependant attenuation of HPV in hypoxia (Left Lower Lobe: 100% nitrogen) Nakazawa K et Amaha K. Br J Anaesth . 1988;60:547. for 50kg: 1µg/kg.min = 3mg/h 3µg/kg.min = 9mg/h 6µg/kg.min = 18mg/h

18. 2.3b Attenuation of Hypoxic Pulmonary Vasoconstriction Effect of nicardipine during experimental hypoxia: more effect on systemic than on pulmonary vasculature in normoxia Nakazawa K et Amaha K. Br J Anaesth . 1988;60:547. for 50kg: 1µg/kg.min = 3mg/h 3µg/kg.min = 9mg/h 6µg/kg.min = 18mg/h

19. 2.3b Attenuation of Hypoxic Pulmonary Vasoconstriction Neutral effect on blood-gas variables during experimental hypoxia: no variation of PaO 2 & PaCO 2 augmentation of PvO 2 in accordance with cardiac output Nakazawa K et Amaha K. Br J Anaesth . 1988;60:547.

20. 2.4 Mechanism of Hypoxic Pulmonary Vasoconstriction Biphasic HPV in isolated PA rings: The initiation of HPV (phase I) is endothelium independent. The second phase of HPV has an endothelium-dependent component to it. Moudgil , et al. J Appl Physiol 98:390-403, 2005

21. 2.4 The “Sensor – Mediator – Effector ” pathway The Redox Theory : Hypoxia inhibits effector O 2 -sensitive Kv channels. Kv channel inhibition activates Ca 2+ entry via L-type Ca 2+ channels . Moudgil , et al. J Appl Physiol 98:390-403, 2005

22. 2.4 Minor influence of CCB on HPV Calcium channel blockers (nifedipine, isoptine , diltiazem): partially blunted phase I, but did not affect phase II of HPV. Hypoxia under control & following preincubation with verapamil Hypoxia under control & following preincubation with nifedine Robertson et al . Journal of Physiology (2000), 525.3, pp. 669—680

23. Origins of Ca 2+ in hypoxic pulmonary vasoconstriction Depolarization - mediated Ca 2+ influx plays at best a minor role in the transient phase I constriction of HPV, and is not involved in the sustained phase II constriction. Phase I appears to be mainly dependent on capacitative Ca 2+ entry (CCE) related to release of Ca 2+ stores. Phase II is supported by Ca 2+ entry via a separate voltage- independent pathway . Robertson et al. Journal of Physiology (2000), 525.3, pp. 669—680

24. 2.4 Role of multiple ion channels in HPV The multiple ion channels Theory : inhibition of voltage-gated K ( Kv ) membrane potential ( Em ) depolarization activation of voltage-dependent Ca 2+ channels (VDCC) activation of inositol-1,4,5-triphosphate receptor (IP3-R) and ryanodine receptors ( RyR ) in the sarcoplasmic reticulum (SR) Ca 2+ release indirectly activating store-operated Ca 2+ channels (SOC) induction of capacitative Ca 2+ entry (CCE) by depleting Ca 2+ from the SR indirectly opening of Ca 2+ -activated Cl ( ClCa ) channels (due to released Ca 2+ ) inducing Em depolarization. Mauban J, et al. J Appl Physiol 98:415-420, 2005.

25. Mechanisms of hypoxic pulmonary vasoconstriction HPV is mediated via K + channel inhibition and Ca 2+ entry in arteriolar smooth muscle cells. Sommer et al . Eur Respir J 2008; 32: 1639–1651

26. 2.4 Mechanisms of hypoxic pulmonary vasoconstriction The effector pathway is suggested to include: voltage-dependent K+ channels L-type calcium channels nonspecific cation channels Mitochondria and NADPH oxidases are discussed as oxygen sensors . Sommer et al . Eur Respir J 2008; 32: 1639–1651

27. 3.1 Hypertensive crisis in hypoxia: understanding Paradoxal augmentation of peripheral resistance ? probably associated with sympathetic hyperactivity (e.g. concomitant with awakening) Classical etiological management of hypertensive crisis: insufficient analgesia awakening hypervolemia urethral obstruction rebound (clonidine) hypothermia / malignant hyperthermia intracranial hypertension Cotte J, et al. Rev Pneumol Clin (2012) Albrecht et al. In “Manuel pratique d’anesthésie”. Ed Masson. 2009

28. 3.2 Hypertensive crisis in hypoxia: management ? Acute respiratory Distress Syndrome treatment guidelines: No mention of hypertensive crisis management Negative fluid balance was associated with better outcome Vasoconstrictors can improve oxygenation in ARDS patients by decreasing intrapulmonary shunt. Hypertensive crisis treatments guidelines: No mention of respiratory distress Role of excessive circulating catecholamines ?? Pierrakos C, et al . J Clin Med Res • 2011;4(1):7-16 Grossman E, et al. Drug Safety 1998;19(2):99-122

29. 3.2 Sympathetic crisis in hypoxia: management ? Dutch guidelines – 2010 revision: Recommended treatment of autonomic hyperreactivity : Phentolamine Nitroprusside, urapidil American recommendations – 2007 update: Recommended antihypertensive agents for sympathetic crisis: Nicardipine, verapamil, diltiazem in combination with a benzodiazepine “experimental studies do not support the use of labetalol in this setting” ! All of these vasodilators could potentially depress the hypoxic pulmonary vasoconstrictor response ! Marik PE et Varon J. CHEST 2007; 131:1949–1962 Van den Born, et al. The Netherlands J of Medicine M ay 2011;vol69(5):248

30. Conclusion: Traditional “British empiricism” as a guideline “ It is concluded that since NG and SNP appear to produce arterial hypoxaemia by depressing the hypoxic pulmonary vasoconstrictor response, their administration should be accompanied by oxygen enrichment of the inspired gases and careful monitoring on PaO 2 . ” D’Oliveira M, et al. Br J Anesthesia 1981;53:11 The experimental and clinical evidences call for a careful approach with all vasodilators without exception. The risk-benefit ratio of vasodilators should always be carefully evaluated in case of hypertensive crisis management in patient with potential pulmonary vasoconstriction . D’Oliveira M, et al. Br J Anesthesia 1981;53:11