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Introduction
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Literature on massive PE focuses mostly on how to deal with the clot while less attention is spent on other aspects of management. This post will focus on such aspects, especially hemodynamic resuscitation of massive PE. There is nearly no clinical data, forcing us to extrapolate between limited data, hemodynamic theory, and experience. This post may be considered a working theory at best.
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#1: Understanding the hemodynamic death spiral of PE
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To save PE patients, first we must understand how they die. Death is due to hemodynamic collapse rather than hypoxemia. The physiology involves RV dilation with impairment of left ventricular filling and hypoperfusion of the right ventricular myocardium.
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PE patients often decompensate rapidly. One minute they will be fine, the next minute they will be coding. Although this may be precipitated by repeated embolic events, I think many of these patients slip into a death spiral as shown above. Once a tipping-point is reached, ongoing deterioration occurs unless intervened upon.
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#2: Volume administration is seldom helpful, and potentially harmful
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Volume management: Theory
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Right ventricular preload (clinically measured as CVP) is a double-edged sword in massive PE. A certain degree of CVP elevation may improve RV filling and cardiac output. However, excessive CVP elevation will over-distend the right ventricle, cause diastolic compression of the left ventricle, and reduce cardiac output. The ideal CVP is probably in the mild-moderately elevated range.
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Traditional teaching is that volume loading is first-line therapy for hypotensive patients with massive PE. However, this makes little physiologic sense. These patients usually have severely dilated right ventricles, and its difficult to understand how dilating the ventricle further could improve its function. When the right ventricle fails, blood naturally backs up and the central venous pressure increases on its own – this is an intrinsic compensatory mechanism which occurs perfectly well without our intervention. Giving additional fluid may cause excessive elevation of the CVP and undue dilation of the right ventricle.
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Volume management: Evidence
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There are no human studies regarding hemodynamics in crashing patients with massive PE. We must extrapolate from the following two studies.
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Mercat 1999 described 13 patients with submassive PE who were challenged with 500 ml of dextran. Although the study refers to these patients as having “massive PE,” this is based on a cardiac index <2.5 rather than clinical criteria. These patients had an average mean arterial pressure of 101mm and patients requiring inotropes were excluded, suggesting that most subjects would clinically meet today's standards of submassive PE. The improvement in cardiac index was inversely related to baseline RV end-diastolic volume:
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Relationship between right ventricular end-diastolic volume index (RVEDVI) and change in cardiac index following 500 ml dextran infusion. A normal RVEDVI is <100 ml/m2.
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The authors concluded that this data supports the use of volume in massive PE, since many patients experienced an increase in cardiac output. However, I would interpret this data differently. Only patients with lower RV end-diastolic volume benefitted from fluid (primarily patients with a normal RV end-diastolic volume index). Imagine extrapolating this data to patients with PE, hypotension, and vasopressor requirement – such patients will have a greater degree of RV dilation and thus little benefit from volume expansion.
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Ternacle 2013 studied the effect of furosemide in submassive PE. This is a retrospective, non-randomized study. Apparently one intensivist used furosemide maintain urine output >0.5 ml/kg/hour, whereas his partners used volume expansion instead (!). The study included 70 patients, with 40 in the furosemide group and 30 in the fluid expansion group. Compared to the Mercat study, these patients had greater RV dilation (the RV/LV ratio averaged 1.2 +/- 0.3, with 72% of patients having severe RV dilation). Patients with underlying systolic or valvular heart disease were excluded. Over the first 24 hours, patients in the furosemide group had improvements in shock index, systolic blood pressure, renal function, oxygenation, and reduction in RV dilation. None of these improvements were seen in patients treated with volume.
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Volume management: Bottom Line?
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Patients with massive PE usually have severe dilation of the right ventricle as well as elevated central venous pressure (as a physiologic response to RV failure). Available evidence suggests that patients with acute PE and severe RV dilation probably benefit little from volume loading. Such patients may actually improve following volume removal. Although this data is sparse, it may be wise to avoid volume loading in these patients until there is evidence that it is safe and beneficial.
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Rarely patients will have shock due to a combination of hypovolemia and PE. This diagnosis can be made on the basis of history as well as examination showing CVP lower than expected for massive PE (i.e., small and collapsible IVC on bedside sonography). Such patients often respond well to volume administration to repair their underlying hypovolemia. Volume administration should be performed judiciously (i.e., in sequential 500 ml boluses) with close monitoring, and stopped promptly if the hemodynamic goals are met or if the patient is not clearly improving responding to volume.
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#3: Consider starting norepinephrine early to maintain an adequate blood pressure
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Part of the death spiral involves hypotension with hypoperfusion of the right ventricle. Therefore, there should be a low threshold to initiate a vasopressor infusion to support the blood pressure. Although the natural tendency is often to treat hypotension with volume administration, a vasopressor may be safer.
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Norepinephrine is a good choice to maintain adequate blood pressure in acute right ventricular failure (Ventetuolo 2014). Note that norepinephrine causes venoconstriction thereby increasing preload. Therefore norepinephrine alone may represent a balanced approach to gently increase preload, improve inotropy, and increase mean arterial pressure. It has been suggested that epinephrine may be superior to norepinephrine because it has stronger inotropic activity and causes pulmonary vasodilation due to beta-2 agonist activity (Boulain 1993). Selection of norepinephrine vs. epinephrine seems to vary based on geography and local practice patterns. This choice is probably less important than the overall strategy of early blood pressure support using a vasopressor with avoidance of excess fluid.
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Absence of central venous access should not delay the use of vasopressors as needed to stabilize blood pressure. Rather than spending time obtaining central access and risking vascular damage (which may become a major problem if thrombolysis is pursued), a better approach may be immediate stabilization with peripheral vasopressor and rapid progression towards thrombolysis.
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#4: For treatment failure, consider inhaled nitric oxide
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Much of the elevation in pulmonary vascular resistance (PVR) may actually be due to pulmonary vasoconstriction due to vasoactive mediators (i.e., thromboxane and serotonin) rather than mechanical obstruction (Smulders 2000). This represents a potential therapeutic target to reduce PVR and improve hemodynamics.
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Inhaled nitric oxide causes pulmonary vasodilation and also improves oxygenation due to facilitation of ventilation-perfusion matching (1). There are several case reports and one case series by Paul Marik describing improvements in hemodynamics and oxygenation following inhaled nitric oxygen. Nitric oxide may be administered via endotracheal tube or face mask. Inhaled nitric oxygen is short-acting and doesn’t cause systemic vasodilation, so it is a safe and reasonable consideration if other interventions are failing. The main drawbacks are availability and cost. Jeffrey Kline is currently studying this intervention and we’ll probably be hearing more about it soon.
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#5: Avoid intubation if possible
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When approaching a crashing patient, an important consideration is always whether to intubate. Intubation is a perilous maneuver for the PE patient, because hypoxemia, hypercapnia, positive pressure ventilation, and sedation may all threaten the patient’s hemodynamics (2).
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It may be best to avoid intubation if possible, or delay intubation until the patient may be stabilized as much as possible. These patients usually die of hemodynamic collapse, not ventilatory failure. Intubation will not fix this problem, and may aggravate it. This is similar to a crashing patient with tamponade or tension pneumothorax, where drainage of the pericardum or pleura may take priority over the airway. If the patient is a candidate for thrombolysis, the best approach may be to delay intubation while pursuing immediate thrombolysis. For patients with poor oxygenation or excessive work of breathing, high-flow nasal cannula may be a safe approach to provide high amounts of inhaled oxygen and reduce the work of breathing (3).
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If intubation is needed, initiation or escalation of norepinephrine infusion beforehand may be wise to establish a hemodynamic margin of safety. These patients are at high risk of a “hemodynamic kill” from intubation; further discussion of avoiding this may be found on the emcrit site.
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#6: Immediately determine contraindications to thrombolysis using a checklist
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It should be determined promptly whether the patient is a candidate for thrombolysis, or whether alternative therapies need to be arranged (i.e., interventional radiology or surgical thrombectomy). A checklist is useful to allow rapid and through evaluation of contraindications. An interactive checklist designed for smartphone use at the bedside is located here.
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If a decision is reached to pursue thrombolysis, heparin should be discontinued (Tapson 2012). Heparin causes no acute improvement in hemodynamics, but increases risk of hemorrhage when combined with thrombolysis. The ideal treatment would be immediate thrombolysis up-front, with initiation of heparin later.
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For a patient with relative contraindications to thrombolysis, half-dose thrombolysis (50 mg alteplase) is a reasonable approach. As discussed in a prior post, half-dose thrombolysis appears to have similar efficacy with improved safety.
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#7: For thrombolytic candidates, pursue thrombolysis early.
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The only intervention supported by evidence as likely improving mortality in massive PE is thrombolysis (4). Consider ordering it early. When a PE patient develops progressively worsening vital signs, this may signal impending arrest. Pharmacy will usually require at least ten minutes to mix up the thrombolytic. Death from PE often occurs within 1-2 hours of onset, so time is of the essence.
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#8: Plan for failure: Know how to code an arresting PE patient
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Even with appropriate management some patients will arrest. With aggressive CPR and prompt thrombolysis, such patients can do well. For example in the MAPPET study, 35% of PE patients receiving CPR survived to discharge.
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There is a nice discussion of the appropriate “code dose” of alteplase (TPA) at the ALiEM site. A reasonable dose for the pulseless patient is a 50mg alteplase bolus. It may take some time for the drug to work, so extending the CPR duration is sensible.
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One phenomenon that seems to occur with PE is a repeated-death phenomenon wherein a patient will receive a bolus of epinephrine, regain pulse for a few minutes, lose their pulse, get another bolus of epinephrine, regain pulse for a few minutes, then lose their pulse again, etc. Hence two suggestions. When the pulse returns, monitor it carefully (either with a finger or arterial-line tracing), and anticipate that it may be short-lived. Second, consider starting a norepinephrine or epinephrine drip early.
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Establishing a definitive airway is a low priority because the primary problem is hemodynamic failure. Compressions should not be stopped to allow for intubation unless there is no other way to ventilate the patient. A laryngeal mask airway (LMA) may be a good approach to facilitate ventilation without interfering with compressions. Video laryngoscopy using a hyper-angulated blade (either a glidescope or CMAC “difficult” airway blade) may allow intubation without interruption of compressions.
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Take-home messages
- The only evidence-based intervention that seems to improve mortality in massive PE is thrombolysis. The primary goal of therapy should be administration of thrombolysis as soon as possible to patients without contraindication.
- Consider early stabilization of blood pressure using a norepinephrine infusion, administered peripherally if necessary.
- Volume administration may facilitate dilation of the right ventricle and hemodynamic deterioration.
- Intubation is very hazardous and should be avoided if possible. Patients die from cardiovascular collapse, and intubation may worsen this.
- For a coding PE patient consider 50mg alteplase bolus as well as an infusion of epinephrine. Patients can do well despite requiring CPR and high dose vasopressor infusions.
Notes
(1) When inhaled, nitric oxide vasodilates capillaries in alveoli which are better ventilated. This preferentially improves perfusion of well-ventilated alveoli, thus facilitating ventilation-perfusion matching. When used in massive PE, it is being used primarily as a pulmonary vasodilator, but improved oxygenation and ventilation are benefits as well.
(2) Hypoxemia and hypercapnia both may cause pulmonary capillary vasoconstriction with worsening of pulmonary vascular resistance.
(3) The anatomic dead space is the volume of air in each breath which never reaches the alveoli and doesn’t participate in gas exchange. Anatomically this is equal to the volume between the alveoli and the source of fresh gas (normally the mouth/nose). High-flow nasal cannula pushes fresh gas into the trachea, thereby decreasing the anatomic dead space (which now shrinks to the volume between the alveoli and, say, the mid-tracheal level). When the anatomic dead space decreases, a greater fraction of each breath reaches the alveoli and the efficacy of ventilation improves. For a patient who is struggling to breathe, improving the efficacy of ventilation means that the patient can actually decrease their minute ventilation and work less hard.
Note that oxygen is a pulmonary vasodilator. Hypoxemic PE patients may experience hypoxemic pulmonary vasoconstriction, with worsening of their pulmonary vascular resistance. Therefore, there should be a low threshold to aggressively oxygenate these patients, for example with high-flow nasal cannula.
(4) There is minimal evidence regarding thrombolysis in massive PE, because this was rapidly adopted as the standard of care. Extrapolating from studies of submissive PE, it is very likely that massive PE patients derive a mortality benefit (compared to submissive PE patients, they most probably have higher benefit with similar risk of hemorrhage).
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"Such patients may actually improve following volume removal."-quote from above This (excellent) article brings to mind a patient I saw recently. I saw a patient 2 weeks ago. 37 years old, previously well with no past medical history. 3 day history of mild SOB and chest tightness. HR 110, O2 Sat 95% on R/A. BP well maintained at ~ 138/86. The patient looked fine. POCUS revealed a normal RV and this was confirmed on a "Formal" ECHO (The ECHO did show borderline Pulmonary Hypertension.) What was unexpected was that on POCUS the IVC was completely collapsed. This was confirmed on… Read more »
Great post! Volume leading to pressure overload and overall worsening is such an extremely important point in massive PE (also important in pt's with underlying PulmHTN). Love the use of nitric oxide as well – if time allows, epoprostenol may be another option (ie takes longer to obtain and set-up but if forward thinking may be option as well – moreover, switching to epo sooner rather than later is important from a cost standpoint- nitric costs approx $12,000 a day at my institution. I like the idea of VPN as well. I use it regularly in combination with norepi or… Read more »
Vasopressin does cause pulmonary vasodilation and systemic vasoconstriction, so using this agent makes sense. The limitation of vasopressin is that at higher doses it causes a lot of systemic vasoconstriction. I have tried this but ran into problems with blue extremities when the dose was increased. So I think vasopressin is a reasonable choice, but there may be limited ability to up-titrate this so its ability to raise the systolic Bp may be limited. It might be a good agent to combine with norepinephrine. I'm unable to find much literature on this, so this is just my opinion. Would be… Read more »
Would vasopressin be a good choice for its purported pulmonary vasodiliatory effects?
In a patient with ongoing CPR what is the best approach: bolus alteplase or ecmo then surgical approach?
Once they are on ECMO (VA) then the emergency is over and you can slow down to decide your Tx (Heparin gtt, IR embolectomy, open surgical embolectmy) but once you give tPA then ECMO cannulation is a mess.
excellent, Josh. just had a 28 y.old male, cardiac arrest in the field. huge rock hard scrotal mass, (suspicious for carcinoma), stat bedside US showed a huge RV w thrombus in the RV, solid scrotal mass, repeating episodes of transient recovery after epi, so i gave 50mg tPA IV push immediately with a very signif improvement overall. even his fixed and dilated pupils recovered, and he began to lighten mentally. started w levophed, but after just having heard a few RV lectures by our friend dr greenwood from philly, i switched over quickly to an epi drip. CT confirmed the… Read more »
Is this an older recommendation, or does it still hold in 2024? the new article is slightly different https://emcrit.org/ibcc/pe/#top.