Hypothermia Protocol and Dialysis

I recently received an inpatient consultation to see a CKD 5D patient. The reason for consult, as is mostly the case with dialysis patients was that he “needs hemodialysis”.

This dialysis patient wasn’t the average bear though. He had had a witnessed cardiac arrest, was treated by EMS, and defibrillated. He had a return of spontaneous circulation after being pulseless for 20 minutes. As soon as he got to the ER, he was initiated on our standard institutional therapeutic hypothermia protocol.  I was called in to dialyze him because (it wasn’t his usual day) the cardiologist wanted to perform a left heart cath on him the following day, and they “did not want dialysis to interfere with that schedule”. My clinical assessment did not reveal a severe degree of volume overload. He wasn’t hyperkalemic, and had only a mild degree of lactic acidosis that was nicely compensated by him being appropriately ventilated. Due to the concerns that I talk about below, I did not see an emergent reason to dialyze him.

I would like to focus on a few teaching points from a nephrologist’s perspective that I took away from this scenario:

1. Therapeutic hypothermia entails cooling post cardiac arrest patients to 32-34 degrees Celsius, ideally within 6 hours of a cardiac arrest.  Both intravascular and surface cooling methods are used. At my institution, the protocol involves administering up to 3 liters of 0.9% saline (which has been cooled to a temperature of 4 degrees Celsius), over an hour. This is complemented by cooling vests. Once target temperature is reached, the cooling phase is continued for 12-24 hours, after which the patient is rewarmed gradually at the rate of 0.5 degrees Celsius/hour.
2. Sub-physiological body temperatures expectedly have adverse effects. Hypothermia can hamper leukocyte function, increasing infection risk later. Cardiac effects include bradycardia and prolonged QT interval (both were present in this patient). Finally, for us nephrologists, here are some adverse effects and pertinent points that we need to keep in mind for such patients:
3. Hypothermia can cause hypokalemia via two different mechanisms. Low temperature causes a transcellular shift of potassium in to the intracellular compartment. This effect is possibly mediated by increased beta adrenergic and sympathetic activity. In fact, hypokalemia in the setting of hypothermia must be repleted extremely cautiously, if at all, given the risk of rebound hyperkalemia as potassium moves back out of the cells when the patient is rewarmed. This rebound hyperkalemia can be frequently fatal due to arrhythmias.
4. The second mechanism by which hypothermia causes hypokalemia is by the induction of polyuria, also known as “cold diuresis”. This hypokalemia is mediated by increased urinary flow, and is seen in conjunction with hypovolemia, hypophosphatemia, and hypomagnesemia. I didn’t observe any of these in my patient, maybe because of his oligo-anuric status at baseline. Nevertheless, close monitoring of volume status and electrolytes is required.
5. Hypothermia interferes with platelet function and with the clotting cascade. In fact, as per this review, 22% of patients had bleeding post-hypothermia induction. That might be a concern when making the decision to dialyze post-hypothermia patients with heparin.
6. The other issue that I ran in to, that was specific to dialysis patients, was the concern about the patient’s temperature. As we know, most HD machines warm blood before returning in to the patient. With most machines, the warmer cannot actually be turned off and only goes as low as 35 degrees Celsius. In other words, dialysis can inadvertently warm the patient up to this temperature (from the target temp of 32 degrees, per the hypothermia protocol)! CRRT machines do have adjustable temp settings that goes down to 32 degrees, so that might be a safer alternative. Given the risk of inadvertently warming the patient, and because I did not see any emergent indication for dialysis, I did not dialyze the patient. I believed that in that situation, his hypothermia protocol took precedence over dialysis.

In my experience, I have observed that referring non-renal physicians often consider inpatient hemodialysis an ancillary service, akin to placing an order for an x-ray or a lab draw. Seasoned fellows have heard this phrase all too often, “I want you to come down and dialyze this patient”. You are then left with the unenviable task of explaining to the non-renal physician that the decision to dialyze would be made by the nephrologist after proper assessment of the patient (isn’t why they consulted you in the first place?). Let’s not allow our familiarity and comfort with dialysis technology lull us in to putting our guard down. Dialysis is an inherently intense and complicated procedure where multiple clinical parameters need to be closely watched. It’s a fact that is often lost in translation.

Posted by Veeraish Chauhan

Renal Grand Rounds - Case of the month

A young woman with h/o polysubstance abuse and seizures was admitted to hospital with status epilepticus. She was treated with a propofol infusion at 5mg/kg/hr which was maintained due to perceived continuing seizure activity. On hospital day 5, she developed an acute metabolic deterioration – rhabdomyolysis : CPK 100,000, AG metabolic acidosis (HCO3 18) and non-oliguric AKI. Her EKG also became abnormal (RBBB). The diagnosis was propofol infusion syndrome.

What is propofol Infusion Syndrome (PRIS)? 

Like many syndromes, PRIS is a conglomeration of clinical and biochemical manifestations.  Based on  83 case reports from 1992-2007, PRIS is characterized by:

1) Metabolic acidosis, (pH less than 7.30 or HCO3 less than 19)

2) Rhabdomyolysis (CPK more than 10K)

3) Renal failure

4) Cardiac dysfunction (Brugada-like EKG pattern, asystole, PEA, sustained VTs, heart failure, or bradycardia) 

5) Hypertriglyceridemia (TG more than 400)

6) Hyperkalemia

7) Hypotension (or use of vasopressor agent)

8) Hepatic transaminitis

9) Hypoxia (PO2 less than 60mmHg). 

The first 5 manifestations are the most common. While there is no requirement for the number of clinical manifestations a patient must exhibit to meet diagnosis for PRIS, a prospective study showed that most patients exhibit at least 3 defining manifestations within 3 days of propofol use.  In the same study, the incidence of PRIS was found to be a low 1% --similar to other estimates.  However, PRIS is associated with high mortality, up to 30% in some studies. Moreover, because many of these manifestations are common, the presence of any of them could be attributed to another etiology, thus delaying diagnosis of PRIS.  For instance, in the case vignette, the initial rise of CK was attributed to seizure rather than PRIS.

Pathophysiology of PRIS

Inhibition of electron flow along the mitochondrial electron transport chain/ impairs oxygen utilization. Propofol or its metabolites inhibits fatty-acid oxidation leading to buildup of toxic fatty acid intermediates. As described in this nice review.

Risks of PRIS?

Critical illness (especially, CNS illness); Use of propofol dosage more than 4 mg/kg/hr —the usual adult maintenance dose is 0.3 to 3mg/kg/hr; duration of Propofol use greater than 24hr; exogenous cathecholamines and corticosteroids; poor intake of carbohydrate, see this reference.

Management of PRIS

Early recognition/diagnosis; Cessation of propofol infusion; Cardiopulmonary support; Hemodialysis (strongly advocated by expert opinion and outcome of case series).  However, there are no known RCT of use of renal replacement therapy in the treatment of PRIS.  Nonetheless, in case series, survivors of PRIS are more likely to have received HD/CVVH.  Therefore, prolonged use of HD/CVVH is worth considering by renal consult service.  Because propofol is lipophilic and has volume of distribution of 20-40L, it is poorly cleared by HD/CVVH, prolonged RRT is likely needed for PRIS management.

The patient in the case was treated with CVVH overnight, and then transitioned to intermittent HD.  At the time of her discharge, she was off HD with her Cr back to baseline.

See this previous post by Nate on PRIS.

Posted by Opeyemi Olabisi