Cardiogenic shock

Cardiogenic shock, a staple of the ICU, is the subject (or a peripheral bystander) of so many CICM SAQs that it would be impossible to list them all. However, a recent SAQ (Question 1 from the first paper of 2023) has catalysed some writing on the subject.

For the revising exam candidate the best resources are probably the most recent SCAI definitions. Califf & Bengtson (1994) is a dated paper, but it appears to be extensively referred to (eg. by virtually every other cardiogenic shock paper) and therefore gets to be called "seminal", which earns it a position in the recommendations purely because there is a reasonable chance a CICM examiner would have read it. The 2020 ESC statement is an excellent free resource for a summary of the management

Definition of cardiogenic shock

How cardiogenic does it have to be? For example, how much of the heart needs to be responsible before you can safely say that the shock is "cardiogenic", and in what way must it be responsible? Is the cardiac output failure associated with acute aortic regurgitation considered cardiogenic shock? What about severe bradycardia, where the contractility is perfectly normal but the heart rate is 25? The number of definitions in the literature appears to be approximately the same as the number of eminent authors, or perhaps more (as a single author may give two different definitions in different papers). The major points of difference appear to be the specificity of the definition of shock, and caveats to the statement. Here are three representative versions:

 "The generally accepted definition of CS is a state in which ineffective cardiac output (CO) due to a primary cardiac dysfunction results in inadequate end-organ perfusion"

- Jones et al (2019)

"A state of tissue and end-organ hypoperfusion caused by the heart’s inability, due to pump failure, to deliver enough oxygen to organs and peripheral tissues to meet metabolic demands in the presence of adequate intravascular volume"

- Krychtiuk et al (2022)

"A combination of low systolic blood pressure (<90 mmHg or a value 30 mm Hg below basal levels for at least 30 minutes), an elevated arteriovenous oxygen difference (>5.5 mL per deciliter), and a depressed cardiac index (<2.2 litres per minute per square meter of body surface area) in the presence of an elevated pulmonary-capillary wedge pressure (> 15 mmHg)."

- Califf & Bengtson (1994)

As one can see, some authors use a rather generic "cardiac cause" statement, which has the merit of being short and memorable. If an exam candidate happens to spout such a motherhood statement in the "rationale" section of their "critically evaluate" answer, it would not look out of place.

Other authors qualify their definition with specific descriptions of where their definition does not apply. These lose the pithy memorability of the generic definitions, and gain nothing by trying to create arbitrary boundaries against other definitions of shock, because the act of excluding them creates preposterous scenarios.  For example, where Krychtiuk et al include "adequate intravascular volume" in their definition, they are basically suggesting that a patient cannot have haemorrhagic shock concurrently with cardiogenic shock. This, plainly, will not do.

Lastly, another version of the same thing calls for strict haemodynamic variables, prescriptively defining the exact cutoffs for parameters such as cardiac output or blood pressure. Not all patients have a PA catheter and therefore not everybody can be diagnosed with cardiogenic shock on the basis of their wedge pressure, but there is something comfortingly authoritative in the hard sharp lines offered by these sorts of definitions. Also, this is the course taken by most trial designers, who need a strict system of enrolment criteria for their cardiogenic shock trials. The 2022 paper by Vahdatpour et al contains a nice table of such trial enrolment criteria, and because we make our decisions on the basis of thse trials, this is perhaps the better set of definition to remember for one's post-exam life:

Cardiogenic Shock Definitions from Landmark Trials

SHOCK (1999)	SBP 30 min or vasopressor support to maintain SBP >90 mm Hg  Evidence of end-organ damage (UO 15 mL/h or cool extremities) Hemodynamic criteria: CI 1<2.2 and PCWP > 15 mmHg
IABP-SHOCK II (2012)	MAP <70 mm Hg or SBP <100 mm Hg despite adequate fluid resuscitation (at least 1 L of crystalloids or 500 mL of colloids) Evidence of end‐organ damage (AMS, mottled skin, UO <0.5 mL/kg for 1 h, or serum lactate >2 mmol/L)
EHS-PCI (2012)	SBP <90 mm Hg for 30 min or inotropes use to maintain SBP >90 mm Hg Evidence of end‐organ damage and increased filling pressures
ESC-HF Guidelines (2016)	SBP <90 mm Hg with appropriate fluid resuscitation with clinical and laboratory evidence of end‐organ damage Clinical: cold extremities, oliguria, AMS, narrow pulse pressure. Laboratory: metabolic acidosis, elevated serum lactate, elevated serum creatinine
KAMIR-NIH (2018)	SBP <90 mm Hg for >30 min or supportive intervention to maintain SBP >90 mm Hg Evidence of end‐organ damage (AMS, UO <30 mL/h, or cool extremities)
ECMO-CS (2022)	Progressive hemodynamic instability necessitating repeated bolus administration of vasopressors to maintain mean arterial pressure > 50 mmHg + impaired left ventricle systolic function (Left ventricle ejection fraction (LVEF) < 35% or LVEF 35-55% in case of severe mitral regurgitation or aortic stenosis) OR all of the following: Cardiac Index (CI) < 2.2 L/min/m2 OR + norepinephrine dose > 0.1μg/kg/min + dobutamine dose > 5 μg/kg/min or Systolic blood pressure < 100 mmHg + norepinephrine dose > 0.2 μg/kg/min + dobutamine dose > 5 μg/kg/min + (LVEF < 35% or LVEF 35-55% + severe mitral regurgitation or aortic stenosis) Lactate > 3 or SvO2 < 50 on two occasions Hypovolaemia excluded (CVP > 7mmHg or PCWP >12mmHg)

SCAI classification and mortality

The Society for Cardiovascular Angiography and Interventions (SCAI) have created definitions to help stratify the severity of cardiogenic shock in order to improve the quality of data collection and clinical trial design. One might liken this development to the Berlin definition of ARDS, or the version 3.0 definition of sepsis. On that basis, it needs to be mentioned in a resource like this, because like the sepsis definitions, CICM may ask about it in their exam.

So: according to the revision statement most recent to the time of writing (Naidu et al, 2022), the following classification was in vogue (see it in full as an image):

• Stage A: At risk. The patient who is not currently experiencing signs or symptoms of CS, but is at risk for its development.
• Stage B: Beginning of cardiogenic shock. Unlike the Stage A patient, this patient has clinical evidence of haemodynamic instability (including relative hypotension or tachycardia). Unlike the Stage C patient, their organs are still functioning well, and tissue perfusion remains good - for example the lactate is normal. Fluid resuscitation is the only intervention they require.
• Stage C: Classic cardiogenic shock. A patient who manifests with hypoperfusion and who requires one intervention (pharmacological or mechanical) beyond volume resuscitation.
  Hypotension (as in Stage B) may be present, but is not required - you can have Stage C shock and be normotensive. Lactate is raised, unlike Stage B, and organ system dysfunction is present (renal failure, LFT derangement, poor mentation, etc). They require one intervention, be it chemical or mechanical.
• Stage D: Deteriorating cardiogenic shock.  These people have Stage C findings, but the parameters of tissue perfusion and organ dysfunction are getting worse. Lactate is rising, biochemistry is worsening, broadly speaking there is a failure of the initial support strategy to restore perfusion.
• Stage E: Extremis; impending circulatory collapse. The words "circulatory collapse" do not mean anything scientifically defined, but like with sepsis and obscenity, you know it when you see it. It describes a state of peri-arrest refractoryness, with lactate in excess of 8.0 mmol/L, unconsciousness, rhythm instability and intermittent episodes of CPR. "Trying to die" was literally the phrase used by Hill et al (2023) in their summary of SCAI stages.

These stages have the merit of being associated with distinct stepwise progression of mortality risk. Hill et al (2023) were able to review about thirty papers to demonstrate this fact. Withour reproducing their table, which contains perhaps more data than the time-poor candidate can handle, perhaps a list with ranges would suffice:

Mortality from Cardiogenic Shock

Stage	Mortality
Stage A	0.8-28.9%
Stage B	2.2-35.1%
Stage C	10.7-59.1%
Stage D	24-66.9%
Stage E	37.7-85.9%

The width and overlap of these mortality ranges should suggest to the reader that there is some heterogeneity in the cardiogenic shock literature, and this would be a perfectly normal thing. There will obviously be a big difference in mortality depending on what the cause of cardiogenic shock happens to be, and Zweck et al (2021) were able to very cleverly identify three major phenotypes, different in their presentation and outcome:

Phenotypes of Cardiogenic Shock

Phenotype	Description	Mortality
Non-congested	Haemodynamically normal, but with poor tissue perfusion and organ function	10-28%
Cardio-renal	Haemodynamically fragile, and with fluid overload and poor renal function	32-45%
Cardio-metabolic	Multiorgan system failure, haemodynamically unstable	53-56%

Which brings us neatly to the causes of cardiogenic shock:

Causes of cardiogenic shock

Borrowing from the chapter on severe heart failure, which overlaps with cardiogenic shock to the point where one may be indistinguishable from the other: 

Causes of Acute Heart Failure Cardiogenic Shock

Vascular Coronary artery disease Aortic dissection Acute valve failure, eg. mitral or aortic incompetence Arrhythmia Pulmonary emboli Infectious Systemic sepsis Endocarditis Myocarditis Neoplastic Infiltration by extracardiac tumour Atrial myxoma Drug-induced Beta-blockers and calcium channel blockers Doxorubicin Alcohol Cocaine

Idiopathic and infiltrative Amyloidosis Peripartum cardiomyopathy Restrictive pericardial disease Congenital Neuromuscular disorders, eg. Duchenne's Congenital heart disease Autoimmune Vasculitis of the coronary vessels Autoimmune endocarditis/myocarditis Sarcoidosis Traumatic Contusio cordis - cardiac contusion Post-operative tamponade Free wall or septal rupture Endocrine and environmental Hypothyroidism or thyrotoxicosis Hypothermia Acidosis and alkalosis Electrolyte derangement

Yes, reader, it is lazy to plagiarise one's own earlier work. And it would be no less lazy to plagiarise the work of others, for example, by stealing this table from Califf & Bengtson. The author takes shelter behind the fact that his own classification appears more comprehensive.

Following from this, any discussion of the assessment and management strategies for a cardiogenic shock patient would be impossibly broad. The CICM exam papers will  usually present the exam candidate with a scenario from which a discussion of cardiogenic shock will follow, focusing the answer on some clinical context. For example, the cardiogenic shock patient in Question 1 from the first paper of 2023 has just come out of the cath lab where you-wont-believe-what-happened. 

Management of cardiogenic shock, in briefest summary

For a variety of possibly bad reasons the author has become taken with a structure that focuses on haemodynamic variables. There is obviously a number of different ways to structure this answer, and the reader is invited to generate their own. The main points which appear to be essential is to include a category for the definitive management of the thing that caused the shock, and to have some dedicated section for the mechanical support strategies, among which one apparently needs to list PEEP. Thus:

Management of Cardiogenic Shock

Definitive therapies to reverse specific pathologies, for example: Repeat angiography and thrombus aspiration Emergency CABG or emergency valve surgery Pericardiocentesis to correct cardiac tamponade Et cetera Medical cardiovascular support Rate: Pacing to maintain AV synchrony Rate aiming at 80-100, to enhance cardiac output If there is diastolic dysfunction or LVOTO, a slower rate may actually be beneficial Rhythm: Maintenance of sinus rhythm and atrial systolic contribution Reverse AF with DC cardioversion or broad-spectrum antiarrhythmics Preload: Crystalloid bolus, aiming at a restoration of circulating volume, guided by TTE/TOE This bolus should be small and careful Decompensated right heart failure with poor  interventricular interaction will instead benefit from fluid restriction and diuresis Afterload: Noradrenaline to produce sufficient systemic vascular resistance to elevate the diastolic pressure and improve coronary perfusion Dobutamine or milrinone to vasodilate systemically and reduce LV afterload Pulmonary vasodilators to decrease RV afterload Contractility: Dobutamine to improve LV contractility Other agents (eg. milrinone, levosimendan) have less evidence in support of them Adrenaline and dopamine seem to be associated with poorer outcomes Mechanical cardiovascular support options PEEP to decrease afterload and improve LV transmural pressure gradient IABP to improve coronary diastolic perfusion VA ECMO as a bridge to cardiac recovery

An attentive reader whose time on this site has included the severe heart failure chapter will recognise these options from that long discussion of heart failure therapies, and to be sure, they are applicable in this lightly modified form, because what is heart failure if not cardiogenic shock but slow? However it must be noted that most of the mentioned options in that chapter are not supported by high level evidence, and the literature for cardiogenic shock is even more vague. Moreover, humming an unnecessarily maudlin note, one could remark that every broken heart is broken in some uniquely horrible way, and large scale trials will always fail to capture the nuance and delicacy of individualised tailored management, guided by a careful hand. What follows is some attempt to scrape together some data to support decisions around cardiogenic shock management, grouped into haemodynamic categories like the summary table above.

Early definitive management for the cause of cardiogenic shock

It does not need to overlaboured, because it is obvious, but somewhere in this chapter it must be noted that early intervention that addresses the cause of cardiogenic shock is the most important influence on the subsequent mortality from it. And we are specifically talking about revascularisation, because cardiogenic shock is mostly ischaemic, unless one's local health district is experiencing an unexplained epidemic of viral myocarditis or cocaine abuse. The evidence for early revascularisation is abundant. In the SHOCK trial (1999), the absolute mortality improvement for early (within twelve hours) angio was 9.3% at 30 days and 21.1% at 6 months, which was maximal for the younger patients (it was in excess of  20% for the under-75s). The subset of patients that ended up getting an emergency CABG had basically the same outcome. In CULPRIT-SHOCK (2017),  an additional 8.2% reduction in mortality was observed when the culprit lesion alone was revascularised, as opposed to multivessel PCI (which tended to produce more AKI). 

Cardiac output monitoring 

Would it help to float a PA catheter? The evidence from the modern era suggests that it would not hurt. The 2020 ESC guidelines cautiously hint that early studies that killed the PAC might have reflected an extinct form of practice, and that these days its use is reserved for "tertiary hospitals with high level of user competence", meaning that it may have greater safety in the right kind of hands. Certainly this seems to be supported by the evidence. Yoo et al (2023) harvested an obscene amount of data from six cardiogenic shock trials (n= 930,530) and observed that the patients in whom PA catheters were used had a trend towards lower mortality. Whether this is because the data generated by the PAC was useful, or the PAC-savvy intensivist was just generally better with inotropes, remains to be determined.

Haemodynamic targets

Irrespective of whether you have advanced haemodynamic monitoring or not, you end up having to decide on some perfusion targets in these patients, as the goal-oriented juniors and nurses will look to you for numbers. Unfortunately there is nothing to guide you here, as none of the eminent societies have ever published a strong recommendation for any specific MAP target. Mattew et al (2022) did an excellent review of this mess, listing all the recommendation from the currently available studies. In short, the Europeans seem to suggest that a MAP of 65 may not be required, and an SBP of over 110 mmHg might even be an indication for the use of a vasodilator.

Optimum heart rate in cardiogenic shock

There is probably no "optimum" heart rate recommendation here, other than to say that extremes of low and high rates are undesirable. Insofar as heart rate factors into cardiac output, one would have to say that in patients with normal left ventricular relaxation characteristics a higher heart rate would be desirable, and would produce a higher cardiac output. At the same time none of these cardiogenic shock patients would have normal LV compliance (having recently infarcted their LV) and none of them would tolerate tachycardia (having probably as-yet-unrevascularised nonculprit arteries), to say nothing of the fact that the drugs we use to increase heart rate are generally arrhyhmogenic. Because of these competing issues, none of the great cardiological societies give any specific recommendations for this haemodynamic variable. Pushed against the wall, most sane people would agree that:

• Some upper-range-of-normal rate would be sensible (80-100)
• No additional chronotropes should be used unless absolutely necessary. Patients with permanent or temprary pacemakers may have their rate manipulated (eg. increased to 80 or 90) to achieve the desired rate.
• To control an undesirably rapid rate, beta-blockers or calcium channel blockers should be avoided (as they are negative inotropes).  Ivabradine  is an option here, as it has no negative inotropic effects, and has been reported as safe in cardiogenic shock.

It is easier to agree on rhythm:

Rhythm control in cardiogenic shock

Broadly everybody will agree that cardiogenic shock patients all benefit from the haemodynamic advantage of normal atrial contraction, and to restore sinus rhythm in them is a laudable goal. The cardiomyopathy may even be caused by the arrhythmia, which makes it even more desirable to return the rhythm to normal. Often these patients will already be intubated, and surrounded by TOE-competent staff, making clot-excluding TOE and direct current cardioversion more convenient. Amiodarone is another option for where an anaesthetic is undesirable. In their review of management options, Maury et al (2019) came to the conclusion that of all the antiarrhythmic agents, amidoarone would be the safest and best tolerated in cardiogenic shock.

Preload management in cardiogenic shock

"Fluid, but less" is the way to describe most learned comments on this subject, as most clinically practicing authors will admit that a fluid bolus will be their first go-to strategy in cardiogenic shock. One may justify this with the statement that cardiogenic shock is usually associated with a period of such desperate unwellness that the patient will be missing some fluid purely because they were too sick to eat or drink, and to restore some of that circulating volume may have some merit. The ESC statement of 2020 suggests a 250ml fluid bolus, because the patient might be "euvolaemic" but may still increase their stroke volume from the extra preload. This is physiologically plausible, but the study they reference in support of this does not seem to contain any supporting data about fluid management. 

Afterload management in cardiogenic shock

The cardiogenic shock patient is often already maximally vasoconstricted and so the use of even more constrictor seems counterintuitive. Moreover the left ventricle would much rather pump against a less resistant circuit, making afterload reduction a more favourable strategy. Squara et al (2019), wisely, point out that the recommendation to use vasoconstrictors in cardiogenic shock rests on the faulty premise that pressure is more important than flow. The bottom line:

• Mean arterial pressure targets probably need to be met with inotropes, not vasopressors
• An inotrope agent with vasodilating properties would probably be ideal for the failing left ventricle
• These agents are often reasonably long-acting and are administered as a continuous non-titrated infusion. During this infusion, MAP fluctuations can be adjusted with vasopressors, the rationale really being a fine control of afterload reduction and to increase the diastolic pressure, and therefore coronary perfusion

Noradrenaline is described as "first line" by the eminent societies, and this makes sense because it has a long history of use in shock, and because it does have some inotropic effect at higher doses. Vasopressin should also not be neglected, as it has little effect (or possibly a beneficial effect) on RV afterload. Neither should be relied upon in isolation, as peripheral vasoconstriction is not the thing that is deficient in these patients.

Inotropes in cardiogenic shock

Let's face it, contractility is really the main issue, and with a dwindling finite supply of cardiac muscle, the only way to get more contractility is to gently encourage the remaining myocytes to work harder. Inotropes are therefore an essential element of management.  The reader in need to an extensive digression into primary exam topics is redirected to these chapters from the cardiovascular section:

• Adrenaline
• Dobutamine
• Milrinone
• Levosimendan

The reason these pharmacology monographs are left here mainly because there is little to discriminate between these agents in terms of patient-centred outcomes, and the choice is usually made on the basis of physiological data, pharmacological principles, anecdotal experiences and weird personal beliefs. Levy (2019) is an excellent authoritative example of a professionally written article that deals with this morass with the patient tone of a mildly exasperated librarian. "The American Heart Association ... surprisingly continues to advocate dopamine use in cardiogenic shock", they chide softly. To concentrate the nutrients in that article:

• Noradrenaline and dobutamine should be first line for cardiogenic shock with mainly left ventricular dysfunction
• Noradrenaline and milrinone should be reserved for cardiogenic shock with mainly right ventricular dysfunction
• Noradrenaline and levosimendan should be considered a second-line therapy on the basis of difficult pharmacokinetics on the part of the latter, and are equally recommendable for both LV and RV dysfunction
• Adrenaline as a solo agent is recommended only for shrt-term support while waiting for expert care,
• Dopamine and vasopressin aren't recommended for anyone, for any reason 

It is hard to know whether there is any point in going into more detail here, particularly with respect to the evidence that is available. The eminent societies certainly do not seem to emphasise trial data in their recommendations. For illustrative purposes only, a selection of RCTs is offered below, which does not purport to be an exhaustive literature review, and which certainly did not aim to find each and every trial on the subject. 

Adrenaline vs. noradrenaline/dobutamine combo (Levy et al, 2011): n=30, merely a pilot. They titrated noradrenaline and adrenaline (around 0.20-0.30μg/kg/minute of each), plus the dobutamine group continued on something like 20 μg/kg/minute.  The same haemodynamic goals were achieved with the combination of catecholamines, but with a much lower heart rate, and with a much faster clearance of lactate. This study, though very small, continues to be quoted in the literature as indisputable proof that adrenaline is a poor choice for cardiogenic shock,

Adrenaline vs. noradrenaline alone (Levy et al, 2018): n=57, randomised and double-blinded; stopped early because refractory shock occurred in 37% of the adrenaline patients, and only 7% of the noradrenaline patients. Lactate and heart rate were also higher with adrenaline. Surprisingly, both agents achieved the same cardiac index improvement. Unsurprisingly, the doses they used were horrific - 0.6 ± 0.7 μg/kg/minute of either agent, corresponding to a range of 40-90ml/hr of standard "single strength" noradrenaline (6mg in 100ml). It is not surprising that noradrenaline at this dose would start having direct inotropic effects, as its selectivity for α1 receptors would surely be lost, and it would behave very much like adrenaline anyway.

In spite of these considerations, the eminent societies have used the two abovementioned Levy papers to recommend in favour of noradrenaline alone as the first line agent in cardiogenic shock. Dobutamine appears to be an afterthought in these guidelines - "inotropes, e.g. dobutamine, may be given simultaneously to norepinephrine in an attempt to improve cardiac contractility", the ESC remark. This may be due to the fact that dobutamine at sensible doses has not been the subject of any trials, whereas noradrenaline at non-sensible doses somehow has. We eagerly await a study where safe amounts of dobutamine are compared to sub-lethal amounts of noradrenaline in cardiogenic shock patients. 

Milrinone vs dobutamine (Mathew et al, 2021; the DOREMI trial): n=192, mainly SCAI-C patients; randomised and double-blinded. They found a 5% difference in absolute mortality (favouring milrinone) which did not reach statistical significance. No other outcomes were much different, including arrhythmias. Biswas et al (2022), massaging the data into a meta-analysis, were inclined to agree with these findings - milrinone appeared to have a generally similar if not ever-so-slightly-better effect on severe decompensated heart failure and cardiogenic shock, as compared to dobutamine. This challenges the assertion that killrinone is somehow intrinsically evil.

Levosimendan is basically an untested drug in this disease (or so it would appear from the lack of trial data). It was only the subject of one RCT, where it was compared to enoximone for some reason (to which it was superior, by a truly preposterous absolute mortality difference of 32%, which is impossible to trust with an n=32, and impossible to generalise with enoximone being unknown outside of Europe). A meta-analysis by Fang & Wang (2018) somehow managed to scrape together 648 patients worth of data from randomised and non-randomised studies and reported an improvement in mortality with an odds ratio of 0.82. It all seems very promising but at this stage levosimendan does not get any love from large international guidelines, apart from being described as being "of interest".