This is the abnormal physiological state which occurs when whole-body ischaemia is followed by whole-body reperfusion. In summary, it is a systemic inflammatory state which resembles every other form of vasodilatory shock; the degree of organ dysfunction depends on the sensitivity of those organs to ischaemia, and the duration of ischaemic time.
Post-cardiac arrest syndrome is a state of multi-organ system dysfunction which follows a period of global ischaemia or hypoxia.
- Pathophysiology is due to three main factors:
- Initial loss of perfusion:
- Anaerobic metabolism in the absence of adequate perfusion leads to acidosis and accumulation of metabolic byproducts
- Resucitation efforts:
- Toxic doses of catecholamines are administered, which exacerbate cardiac injury and degrade peripheral perfusion
- Direct current is administered to the myocardium, which exacerbates cardiac injury
- External compressions are performed, causing trauma to cardiac structures
- Manual breaths are administered, which promotes aspiration
- Reperfusion following ROSC:
- Redistribution of regionally accumulated metabolic byproducts into the systemic circulation leads to a systemic inflammatory response
- Systemic inflammatory response cytokines aggravate endothelial injury and organ dysfunction
- Specific organ system dysfunctions:
- Brain injury, probably mainly due to anoxia but with some contribution from microcirculatory thrombosis
- Myocardial dysfunction (usually global, adding to whatever myocardial disease might have had precipitated the arrest)
- Vasodilation and endothelial dysfunction due to systemic inflammation
- Respiratory failure due to aspiration and capillary leak-related ARDS
- Renal failure due to tubular ischaemia
- Hepatic dysfunction due to hepatocyte ischaemia
- Coagulopathy due to endothelial dysfunction (possibly even DIC)
- Bacterial translocation from the intestine, leading to worsening SIRS
- Time course:
- Injury due to the loss of perfusion and reperfusion injury are seen in the first minutes and hours
- Organ system dysfunction plays a role in the first few days
- These represent opportunities for interventions which could potentially reverse some of the pathological pathways
- Following these days, the resolution of organ dysfunction permits more confident prognostication
This disease process is sufficiently common in the ICU that one might have expected it to appear somewhere in the past exams, but CICM have never explicitly included it in a written paper or viva, making this chapter a nonessential culdesac. The reader whose interest in their job extends slightly beyond the need to pass exams will probably ask for more detail and a more professional approach to the subject than would be normally expected of a Deranged Physiology page; these discerning consumers are redirected to the excellent review literature by Nolan et al (2008), Binks & Nolan (2010), Mongardon et al (2013), or Nolan & Newmar (2009). In case you're noticing a trend, basically anything with Jerry Nolan in the list of authors seems to be gold.
In the 1960s and 1970s, Vladimir Negovsky ("the Reanimator") published a lot of material concerning a new disease entity, which has arisen largely as a result of advancement in resuscitation techniques; he called it "postresuscitation syndrome".
Now, resuscitation techniques had not advanced all that far. The papers shed some light on some of the unusual practices of the critical care specialists of the old USSR. For one, fluid resuscitation of the arrested patient was performed as an intra-arterial infusion of whole blood, mixed with glucose, adrenaline, and hydrogen peroxide (as an oxygen donor). But the observations, performed on animals, were sound.
Subsequent decades have brought about an improvement of resuscitation techniques, and a better understanding of the pathophysiological processes which take place in the body of the recently reperfused. In the west, people have also stopped calling this science "reanimatology", perhaps because of the Lovecraftian connotations of the term.
But getting back to topic, post-cardiac arrest syndrome is a well-described collection of organ system malfunctions which occur together after a period of global ischaemia. One can presume that the most ATP-hungry tissues would suffer most, and this is indeed the case in most circumstances. Additionally, a systemic inflammatory response develops, because the vascular endothelia respond to ischaemia and reperfusion by becoming dysfunctional, just like in septic shock. On top of that, the primary problem - whatever caused the cardiac arrest - is still in play; given that it is most frequently a myocardial infarction, one can expect a cardiogenic shock to develop. Lastly, "true" septic shock may develop as the reperfused gut loses its integrity, and gut bacteria cross into the systemic circulation.
With the flow of oxygenated blood now ceased, the cells have little reserve. There isn't much intracellular oxygen. Some, as in muscle, is stored in myoglobin (and is therefore available to ischaemic muscle) - but the rest of the cells, particularly important cells like neurons, have little oxygen in the cytoplasm - whatever is dissolved in the cell water, with a partial pressure of maybe 1-3mmHg.
The other reserve of oxygen is contained in the capillary blood, the only blood available for gas exchange. Only about 5% of the circulating volume is in capillaries, and so one can imagine that for a 70kg person only about 250ml of oxygenated blood is available for gas exchange when circulation ceases.
ATP must be made. This stash of oxygen is chewed up pretty fast. One author suggests a time frame of 20 seconds.
As oxygen is depleted, the tissues switch to anaerobic metabolism in an attempt to sustain some vital functions, but this is an inadequate process, and the demand for ATP is too great. The lack of ATP leads to a breakdown of basic cellular processes. This is the familiar pattern of ischaemia, characterised by the collapse of transmembrane concentration gradients and the generation of free radical molecules.
The time frame of this period is more elastic. Of course, with CPR in progress, some oxygen will reach some tissues; this could be described as a "low flow" state. During CPR the process of ischaemia can be reversed to some extent (in fact that's really the point - if oxygenation of the myocardium can be restored, it can potentially be defibrillated, or stimulated with adrenaline).
Now, let us consider the end of resuscitation. Spontaneous circulation is restored, and oxygenated blood returns to the oxygen-starved tissues. However cheerful this may be, some damage has already been done.
In addition, a degree of reperfusion injury occurs, resulting in lipid peroxidation and apoptosis.
When widespread, the combination of global ischaemic injury and global reperfusion injury results in a vast amount of free fatty acids, free radicals, lipid fragments and spilled cellular contents, all floating in the bloodstream. On appreciating this situation, the immune system becomes enraged. Complement is activated, and endothelial cells express adhesion molecules and chemokines; leukocytes flood the bloodstream with proinflammatory molecules.
This situation results in multi-organ system failure, and I will now make an attempt to discuss the more relevant organ systems in individual detail.
Having spent some time without oxygen, the tissues of all organs are going to work abnormally.
The summary of this busy diagram is that basically nothing works. On top of that, dysfunction begets dysfunction, and without attention this whole process leads to worsening tissue perfusion.
Much of this is due to hypoxia-induced endothelial activation. The endothelium is a hypoxia-resistant beast; these cells can survive very low oxygen tension by adjusting their patterns of metabolism. This, initially, is a protective mechanism; but if hypoxia is prolonged and severe, other mechanisms come into play, and the endothelial response becomes pro-inflammatory. This closely resembles the shock syndrome of sepsis, and the hypotension is similarly responsive to noradrenaline.
The recently massaged myocardium is not a well organ. In pig studies at least, ejection fraction decreases from 55% to 20%. Six or so hours after the cardiac arrest, poor cardiac output really begins to contribute to hypotension.
However, this is a reversible phenomenon. After 48-72 hrs, myocardial function returns to normal. Furthermore, while it is happening it is readily responsive to inotropes.
In addition to this, there is the primary insult - remember that the majority of these arrests are due to a major coronary occlusion event (48% according to a NEJM article, 70% according a French article in Circulation). The area affected is usually sizeable.
Ischaemic damage to the adrenal glands does nothing for the wellbeing of one's hypothalamic-pituitary-adrenal axis. Studies of post-arrest patients have demonstrated a failure to respond to ACTH, which has been interpreted as a relative adrenal insufficiency (although the circulating levels of cortisol may actually be elevated into the abnormally high range, its still not enough!). However, this adrenal insufficiency has not yet prompted any calls for standard administration of corticosteroids to post-arrest patients. One may consider this only if the shock state is unresponsive to vasopressors (much the same as in sepsis, in fact).
This, after all, is where the money is. The neuronal damage after cardiac arrest occurs over hours or days, and thus offers a large timespan over which the intensivist may try to intervene. Some of the damage is related to migratory hypoxia which occurs during CPR, where the blood flow to the cerebral hemispheres is fluctuating between absent and low. After about 15 minutes of downtime, other factors come into play; the most interesting of these is probably microthrombosis (probably more due to stasis than to endothelial dysfunction). Could we thrombolyse that? The TROICA trial addressed this problem; there are no published results, but personal communication from the investigators to the ILCOR group had answered this question with a convincing "no".
After restoration of circulation, the cerebral bloodflow autoregulation mechanism is impaired. The result is cerebral vasodilation and hyperemia. During this phase (which can last for hours) too much oxygen is potentially a very bad thing, as it will increase the generation of free radicals, and thus neuronal lipid peroxidation.
However, overall, the ILCOR people conclude that cerebral bloodflow after cardiac arrest is usually sufficient to meet the demands of oxidative metabolism, and this is supported by the finding that nimodipine infusion does not improve neurological outcome in these patients.
The renal medulla normally functions at the threshold of maximal oxygen extraction, and so it would stand to reason that in cardiac arrest this hungry tissue would suffer considerably. indeed, it seems a good proportion of post-arrest patients develop an acute kidney injury, particularly if the downtime was prolonged, r if they develop significant cardiogenic shock, or if they clog their organs with the microthrombi of DIC. However, local investigators from Melbourne have demonstrated that among non-cardiogenic shock arrest survivors this complication is surprisingly rare. In a recent case series, about 7% of out-of-hospital cardiac arrest survivors received hemodialysis.
In any case, what would you do about it. Your fluid management and vasopressor support is already optimised to improve perfusion to the heart and brain, so the kidney benefits as a bystander. You really cannot avoid a certain amount of nephrotoxicity, as you will inevitably have an angiogram with contrast, and the threat of renal failure would not be an obstacle to this critically important procedure. And of course, if it really gets out of hand, one can always offer the patient some dialysis.
Apart having their stomach lacerated or ruptured during CPR, post-arrest patients can suffer ulceration of the gastric mucosa. This mucosa is another oxygen-hungry organ, which requires normoxia to maintain its normal protective function. As hypoxia develops, the mucosa is unable to defend itself from the acidic contents of the stomach, and gastric mucosal injury occurs. Certainly, with their NG tube on free drainage, we often see brown material oozing up out of the patient's stomach, and we all conclude that this must be the coffee-grounds of diffuse mucosal injury. However, in the literature there is little evidence to suggest that cardiac arrest on its own is a significant risk factor for stress ulceration. In fact, the guidelines for stress ulcer prophylaxis do not list it as one of the major indications.
Of all the sphincters which could fail you, this one is surprisingly the most embarrassing. Consider that cardiac arrest patients are rarely so polite as to dutifully fast themselves prior to their near-death experience, and thus are usually with an at least partially full stomach when the reaper arrives.
Consider what we do to them. Consider that while CPR is in progress, they are lying supine; and somebody is compressing their chest, very near their epigastrium. Consider that which chest compressions are in progress, an anaesthetics trainee is bagging air into their chest cavity with powerful, confident pumps of the bag. This is supposed to happen between compressions, but in the frenzy of resuscitation it is typically an asychronous process. If a compression of the chest is occurring at the same time as a bagged inspiration, all of the bagged air will not be able to enter the compressed chest, and will take the path of least resistance into the stomach, past the relaxed sphincter.
As this process continues, the stomach becomes filled with air. Gastric contents sloshes up and down the oesophagus, and is aspirated into the lungs. And then you intubate the patient, and blow this acidic filth all over their bronchial tree.
In short, the loss of lower oesophageal sphincter tone during resuscitation is actually a really bad thing.
So, the failing ventricle has backed up like a sink and your lungs are filling with the froth of pulmonary oedema. This oedema mingles with the aspirated stomach contents, which has been ventilated all over the pulmonary parenchyma. Vigorous CPR has added to this by causing pulmonary contusions. And lastly, the whole-body ischaemia and reperfusion injury has resulted in a global endothelial dysfunction, which also includes a dysfunction of the pulmonary endothelia.
In short, there are plenty of reasons to develop an ARDS-like respiratory failure following a cardiac arrest.
ILCOR cannot recommend any specific ventilation strategy. They merely point out that the management of this sort of respiratory failure will likely be somewhat different to the management of straightforward ARDS. Low tidal volume ventilation in ARDS typically leads to a reluctantly tolerated hypercapnea. This would not be useful post arrest, as you would be obsessively monitoring the PaCO2 and aiming at strict normocapnea to prevent excessive cerebral vasodilation.
Thankfully, therapeutic hypothermia decreases the whole-body metabolic rate, and thus decreases the amount of CO2 produced by the tissues, reducing the minute volume requirements, and permitting the use of lower tidal volumes.
Like with everything else, the cessation of blood flow during cardiac arrest tends to cause some degree of hypoxic liver injury. When circulation is restored and a low-flow shock state prevails, the liver finds itself again starved of sufficient oxygen, as the mesenteric circulation is particularly sensitive to an activated renin-angiotensin-aldosterone system. The typical features of ischaemic hepatitis are the initial elevation of bilirubin and transaminase enzymes, which is followed by the elevation of cholestatic enzymes (as the ischaemic liver swells, bile duct flow is decreased). Given that it seems to be more closely associated with right heart failure and hepatic venous congestion rather than with the shock state itself, one might presume that careful management of inotropes and fluids to improve cardiac output will be the most hepato-protective thing you could do.
Intestinal ischaemia occurs as a result of cardiac arrest. The gut, deprived of oxygen for a period, suffers along with the other organs; however unlike the other viscera, this one contains teeming legions of hostile organisms. Delighted, they pour through the stunned defence networks of the gastrointestinal mucosa, and invade the bloodstream. Some studies agree that gram-negative bacteria are the most common bacteraemia in cardiac arrest survivors; however pneumonia is still the most common infectious complication, and Staph aureus is the most common clinically relevant pathogen.
There is a known tendency among survivors of cardiac arrest to develop infectious complications in the ensuing 24 hours. In fact, it seems 2/3 of them develop some infection or other, but this does not seem to influence their mortality. In fact, the Swedish Hypothermia Registry reports that although 41% of the patients developed pneumonia, only 4% went on to develop sepsis. Thus, the AHA cannot recommend antibiotic prophylaxis at this time.
Some of the propensity towards sepsis may actually be the consequence of therapeutic hypothermia, but it does not appear to be an important concern.