Pulmonary hypertension (PH) is a chronic disease associated with significant morbidity and mortality, responsible for approximately 15,000 deaths per year in United States.1 The deleterious cardiac effects associated with PH (e.g. Right Ventricular disease) render this population particularly susceptible to decompensation. Hypoxemia, acidosis and hypercapnia are not well tolerated in PH and will acutely increase pulmonary artery pressures, leading to hemodynamic collapse.2
This is especially problematic as this instability is further exacerbated by standard resuscitation practices. Despite an evident increase in research regarding the resuscitation of acute decompensated PH, many emergency medical services (EMS) protocols, paramedic education programs, emergency medicine residencies and critical care fellowships still fail to highlight the clinical importance of PH in resuscitation – subjecting this patient population to significant harm.2 The purpose of this review is to provide an overview of PH, outline the relevance of PH to EMS and help guide the development of future EMS protocols and education programs.
PH is definitively diagnosed by right-sided heart catheterization to assess mean pulmonary artery pressure (mPAP). Normal mean pulmonary artery pressure (mPAP) is defined as 14 +/- 3 mmHg, with PH being defined as a mPAP > 25 mmHg.3 PH is then subdivided into five groups based on specific pathogenesis, each with unique treatment trajectories. Group One PH is a result of pathologies causing direct harm to the pulmonary arteries and is frequently referred to as pulmonary arterial hypertension (PAH).
PAH is further divided into the following subgroups: heritable pulmonary hypertension, drug induced PAH, PAH associated with connective tissue disorders, portal hypertension, HIV infection, Schistosomiasis, congenital heart defects and idiopathic cases of PH. Group Two PH is a result of left sided heart disease, while Group Three is PH second to obstructive lung diseases such as Chronic Obstructive Pulmonary Disease (COPD). Together, Groups Two and Three make up the majority of PH cases.4
Group Four PH arises from coagulation issues and pulmonary artery obstructions and is the only potentially reversible form of PH. Lastly, Group Five PH refers to cases that do not fit any of the previous categories. Group Five cases are often complex and multifactorial and are split into four broad categories including: hematologic disorders, systemic disorders, metabolic disorders and other disorders.3
Identifying the specific subtype of PH is not reasonable in the prehospital setting; however, a general understanding of the breadth of possible etiologies and subsequent inquiry by prehospital providers may help guide treatment strategies in pre-hospital shock resuscitation.
Pathophysiology of Pulmonary Hypertension
Pulmonary hypertension (PH) is a progressive disease. Prognosis is directly related to the speed of disease progression and the ability for the body to compensate against increased pulmonary vascular resistance (PVR).5 Increased PVR is the downstream result of the distinct underlaying condition that lead to PH. Over time, the right ventricle undergoes hypertrophy to maintain cardiac output (CO) in the face of elevated PVR.6
However, chronic exposure to increased PVR and elevated right ventricular pressures eventually results in dilation of the right ventricle through backflow from the pulmonary vasculature across an incompetent pulmonic valve. Dilation of the right ventricle is indicative of end-stage PH and is associated with poor prognosis and significant risk of hemodynamic collapse.7 Hemodynamic compromise in this stage results from right ventricular failure and subsequent reductions of CO below homeostatic levels.
This may occur as part of the natural progression of the disease or may be precipitated by a number of external triggers such as noncompliance with medication, excessive salt intake, infection, or acute thromboembolic events (e.g. pulmonary embolism).8
Mechanisms Behind Right Ventricular Failure and Hemodynamic Collapse
Acute exacerbations of PH from either natural disease progression or external triggers require specific interventions that necessitate a foundational understanding of the pathophysiology leading to right ventricular failure and hemodynamic collapse. These treatment strategies may significantly differ from the care of similar conditions in patients without PH – particularly in the management of septic shock.9
Hemodynamic compromise occurs when the right ventricle can no longer compensate against increased PVR and subsequent dilation of the RV occurs second to backflow from the pulmonary vasculature. In a normal heart, expanded volume yields an inotropic effect and increases stroke volume (SV) via the Frank-Starling Mechanism. However, once the right ventricle is expanded beyond a critical point, SV will decrease worsening backflow and ventricular dilation.
The over-expanded right ventricle causes the interventricular septum to bulge into the left ventricle (LV), resulting in decreased left ventricular SV and reduced cardiac output (CO) in a phenomenon called interventricular dependence.10 At the same time, tricuspid valve regurgitation increases right atrial pressure, leading to further reduction of LV preload and subsequent impedance of CO.11 Adding to the insult on compensatory mechanisms, high atrial pressures at this point may render a formerly asymptomatic foramen ovale to become patent and allow interatrial mixing, affecting blood oxygenation.12
Additionally, this physiology has adverse effects on the perfusion of the right coronary artery (RCA). Under standard conditions, blood flow to the RCA relies on a pressure gradient between the aorta and the RV, during systole and diastole. As RV pressures approach systemic pressures in acute decompensated PH, there is substantial risk of RV ischemia through several mechanisms out of the scope of this review. This resulting mismatch between oxygen supply and demand reduces RV contractility, leading to further reductions in CO.13—15
The previous cascade produces diastolic and systolic right heart failure, which can lead to multi-organ failure. Specifically, renal failure arises through sympathetic activation of the renin-angiotensin-aldosterone system and endogenous vasopressin release, which together impair perfusion through fluid retention and arterial vasoconstriction.5 Overall, this volume overloaded state with associated hemodynamic collapse requires a complex and unique approach to prehospital shock resuscitation.
Identification in the Prehospital Environment
Identification of PH in the prehospital arena is difficult and relies heavily on past medical history. In the absence of a self-reported reported diagnosis, several factors may help identify patients with PH. Prescribed calcium channel blockers, endothelin receptor antagonists, phosphodiesterase-5 (PDE5) inhibitors and prostanoids are all common in the treatment of PH (See Table 1).4
However, these medications are not solely used for PH and subsequently do not definitively indicate a past diagnosis of PH. Additionally, patients with a history of COPD, left-sided heart failure, connective tissue disorders, thromboembolic disease, or low socioeconomic status have a higher prevalence of undiagnosed PH.4
Common electrocardiogram findings include right axis deviation, right ventricular hypertrophy, right bundle branch block or T-wave inversion, although ECG lacks the sensitivity and precision to possess diagnostic value.16,17 As a result of non-descriptive physical exam findings, it is imperative for prehospital providers to obtain a full medical history from the patient or family when making decisions regarding resuscitation management.
In the emergency department, ultrasound has been increasingly utilized in the identification of various pathologies and is positioned to continue to expand its role in the near future.18 Although definitive diagnosis of PH requires right heart catheterization, ultrasound may play a role in the emergent setting.2,16 The apical four chamber and parasternal short axis views identify the presence of RV dilation and septal bulging respectively and have been successfully used to guide resuscitation in the emergency department.19—22
Formal echocardiography, including tissue doppler, may be superior, but is not realistic in the emergency department or prehospital setting. Furthermore, ultrasound in the prehospital setting is currently limited to simple yes/no diagnoses such as the presence or absence of cardiac activity.23 As a result, the recognition of RV dilation and septal bulging are likely unrealistic and would require extensive training.
An alternative to rigorous training is the use of tele-ultrasound (TUS), which allows paramedics to perform ultrasound under the guidance of an emergency physician, who will ultimately interpret the findings.24,25 The ability of emergency physicians to guide and interpret this form of ultrasonography currently varies by institution; however, this skillset may become universal as the role of ultrasound in emergency medicine continues to grow.26
The resuscitation of patients with PH presenting in shock is particularly complex. In the setting of septic shock, patients may be subject to harm if treated with traditional sepsis protocols.2 In general, guidelines suggest an initial crystalloid fluid bolus of approximately 30cc/kg or 1-2 liters.27 In a normal patient, this fluid increases perfusion through raising both CO and mean arterial pressure (MAP). However, in the setting of PH, large fluid boluses will exacerbate dilation of an already volume overloaded RV, leading to greater interventricular dependence and a subsequent reduction in CO.2
Additionally, RV dilation due to volume-overload will raise RV pressures. As RV pressure approaches systemic blood pressure – which is likely low in the setting of shock – RCA perfusion will decrease as a result of reliance on diastolic filling.3 Likewise, in other shock etiologies, large fluid boluses will have similar detrimental effects. Therefore, prehospital shock resuscitation in the setting of PH should cautiously employ fluids, limited to small 250cc boluses, only when there are clear indications of volume depletion.2
The use of vasopressors in the management of acute decompensated PH is complicated and guided by a sound understanding of physiology. Patient’s in shock second to decompensated PH will present with increased PVR, decreased SVR and poor myocardial contractility – all resulting in reductions in CO. As systemic hypotension is extremely detrimental in these patients due to the reduction of RCA perfusion described above, vasopressors must be employed early in the course of care (See Table 2).
In many states, EMS is not permitted to administer vasopressors via intravenous infusion in the field and is limited to the use of Push-Dose-Epinephrine (PDE). Traditionally, PDE is used as a temporizing agent to raise blood pressure in peri-arrest patients who are exhibiting signs of shock and hemodynamic collapse. In PH, the threshold to use PDE may be lower as PDE could be a suitable answer to increasing systemic blood pressure above RV pressures in an effort to maintain RCA perfusion; however, this has not been studied to our knowledge and should be employed cautiously.28
Additionally, epinephrine has important considerations for use in patients with PH. With alpha and beta effects, epinephrine will increase CO and SVR, but comes with an increased risk of tachydysrhythmias and increased PVR.29,30 Tachydysrhythmias are particularly harmful in this population as they reduce ventricular filling times, thus reducing CO.29,30
As a result, tachydysrhythmias encountered in the setting of PH should be promptly addressed. Several studies have shown that conversion to sinus rhythm, not rate control alone, is important in the cohort.31 With the determinantal effects of systemic hypotension in these patients, electrical cardioversion may be preferred to chemical cardioversion.
In EMS agencies that allow for intravenous infusion of vasopressors, norepinephrine is generally accepted as the first line treatment when distributive shock is suspected.27,32 As a strong alpha one agonist, norepinephrine will help offset hypotension by increasing SVR. At the same time, norepinephrine may increase PVR, a potentially harmful side effect in PH. Norepinephrine, like epinephrine, has some beta-1 effects, but they are not as profound and have not been associated with an increased risk of tachydysrhythmias.29
Recent evidence has suggested that vasopressin may be a first line agent for resuscitation of decompensated PH. Low-dose vasopressin has been found to increase SVR through V1 stimulation, but unlike norepinephrine, it also provides a reduction in PVR.33 The combination of increased SVR with decreased PVR makes vasopressin a potential first line agent in PH resuscitation, although further research is required.
As an alpha-1 agonist, phenylephrine has non-selective vasoconstrictive effects on both systemic and pulmonary vasculature, resulting in increases in both SVR and PVR without an effect on heart rate or contractility.34 The associated increase in PVR with the administration phenylephrine is potentially deleterious in this patient population as it will further increase RV workload, leading to reductions in CO.
Dopamine is the biological precursor to norepinephrine and its effects are highly dependent on dosing. At low doses (3-5mcg/kg/min), dopamine produces systemic vasodilation and increased blood flow to the renal tubules, resulting in sodium excretion and increased urine output. At moderate doses (3-10 mcg/kg/min), dopamine has positive inotropic and chronotropic effects through beta receptor stimulation. High doses (>10 mcg/kg/min), produces systemic and pulmonary vasoconstriction through alpha-1 stimulation.
The pulmonary vasoconstriction may increase PVR and worsen RV failure; however, studies examining this theory are mixed.35—37 Additionally, tachydysrhythmias are reported in about 25% of patient receiving dopamine, which is especially harmful in PH as described previously.38
Due to reduced RCA perfusion and rising PVR, inotropes may be required. The most commonly used inotropes in this setting are epinephrine, dobutamine and milrinone. Dobutamine belongs to a class of drugs referred to as inodilators, meaning it has agonistic effects on both beta one and two receptors, leading to an increase in heart rate and contractility and a decrease in SVR. As a result of the potential risk for hypotension, dobutamine should only be employed in this setting if a vasopressor is running to offset the decrease in SVR.29
Like dobutamine, milrinone is also an inodilator. However, milrinone produces an increase in contractility and a decrease in SVR through phosphodiesterase inhibition, not beta stimulation. In theory, this should carry less risk of tachydysrhythmias, a concern for the use of dobutamine in this setting.29 Additionally, nebulized milrinone may be of use to achieve a reduction in PVR without the associated risk of hypotension.39 However, this route of administration will not increase myocardial contractility to the same degree.
Epinephrine can also be employed to produce positive inotropic effects. Epinephrine effects both beta 1 and 2 receptors, although as an alpha-1 agonist, it offsets the beta-2 reduction in SVR and typically yields a net increase in SVR.30 As described above, epinephrine is potentially harmful in the population due to its risks of tachydysrhythmias and increased PVR.
Overall, in a perfect world there would be a single agent that would achieve a reduction in PVR associated with an increase in SVR and myocardial contractility. To our knowledge this agent does not exist and hemodynamic management must rely upon a complex combination of a variety of vasoactive medications. Therefore, prompt transport to a tertiary center with PH specialists is extremely important.
Oxygenation in patients with PH is especially important. Even transient hypoxia in this cohort can raise PVR and accelerate the cascade of events leading to hemodynamic collapse through a mechanism called hypoxic pulmonary vasoconstriction (HPV). HPV is generally a beneficial mechanism that shunts blood to only well-ventilated portions of the lung, optimizing oxygenation.
This is especially important in compensation of chronic lung diseases such as COPD. However, HPV also results in an increase in pulmonary artery pressure, presenting a risk to patients with PH.40 In order to combat this process, high flow oxygen via non-rebreather mask should be promptly initiated and may be supplemented with an additional high flow nasal cannula.41 Patients should also be placed in a semi-fowlers position to avoid increased PVR associated with supine positioning.42
If oxygen saturations still do not climb with use of the non-rebreather and nasal cannula, Continuous-Positive Pressure Ventilation (CPAP) should be employed with the lowest possible Peak-End-Expiratory-Pressure (PEEP), generally 5 cm H2O.43 Higher PEEP may increase pulmonary artery pressures.43—45 If these methods still do not raise oxygen saturation, intubation should be considered. Typically, early intubation in patients presenting with severe shock is recommended in efforts to better control a patient’s ventilation, oxygenation, hemodynamics and airway protection.
In the case of PH, this may approach may be detrimental.2,16,43 In fact, the use of mechanical ventilation in PH has been previously associated with a 26.5% increase in mortality.46 Patients with PH are particularly susceptible to the effects of positive pressure ventilation (PPV) as PPV causes an increase in intrathoracic pressure, resulting in higher pulmonary artery and RV pressures. PPV also contributes to hyperinflation of the alveoli which compress pulmonary vessels, raising RV afterload.16
Additionally, induction agents used in rapid sequence intubation (RSI) are often associated with hypotension and poor cardiac function which as described previously reduces RCA perfusion.47,48 RSI may also cause hypoxia and hypercapnia during laryngoscopy, which is especially harmful in this patient population.49 To avoid hypoxia, pre-oxygenation with a high flow nasal cannula (15 lpm) should be employed. CPAP may also be of benefit in the pre-oxygenation of these patients as it provides a low level of positive pressure which will minimize the shock experienced by the body when PPV is initiated after intubation.42
If intubation is to be performed it should be after exhausting other methods of oxygenation and be performed by the most experienced intubator with careful attention paid to agents selected for induction. Etomidate and ketamine are generally preferred over propofol as the risk of hypotension is significantly less.42 Additionally, some evidence suggests an awake approach to intubation may be preferred in patients at risk of hemodynamic collapse.42
Once a patient is intubated ventilator settings should follow the lung protective strategy with several caveats.50 Hypercapnia is generally well accepted in most patients, but is harmful due to exacerbations of HPV in this setting.51 Therefore, the respiratory rate should be set higher than typical guidelines at around 16 bpm as opposed to 10-12 bpm. Additionally, minimal PEEP (<12 cm H2O) should be used in an effort to avoid an increase in pulmonary artery pressure.1
In summary, airway management in PH differs significantly from typical resuscitation and is particularly sensitive to transient hypoxia and hypercapnia. As a result, close attention should be paid to the oxygenation and ventilatory status of these patients.
Resuscitation of patients with acute decompensated PH is complex and often does not receive adequate attention in the prehospital field. In spite of this, it is important that PH is recognized prehospitally as resuscitation by standard protocols will cause harm to this population before they ever arrive at the emergency department doors. EMS agencies, institutions and providers should increase awareness of the special considerations for resuscitation in this population as well as conduct future research to understand the best approach to the management of this condition in the prehospital environment.
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