Episode Transcript
Hello to everyone listening. My name is Dr. Jacob Bolyard. I am currently a CA3 resident at Loyola University Medical Center. I will be continuing my training at the Cleveland Clinic next year as an adult cardiothoracic anesthesia fellow. This talk will focus on enhanced recovery after surgery, and more specifically, after cardiac surgery. I am accompanied by Dr. Michael Majewski. Dr. Majewski is the current residency program director at Loyola. He completed an adult cardiothoracic anesthesia fellowship at Northwestern, and is also a part of our acute pain service.
Hello. It is a pleasure to be with you today talking about what anesthesiologists can do to enhance postoperative recovery in cardiac surgical patients.
There are currently a ton of exciting areas of research and new practices that are being borrowed from non-cardiac surgery and applied to the cardiac world. I think a good place for us to start is with the drug methadone. First, we will review what methadone is and how it works, then we’ll discuss its utility in cardiac ORs.
Methadone is a long acting mu receptor agonist that also has some NMDA antagonist activity which may potentiate the mu-receptor effects and help prevent opioid tolerance. It also has agonist activity at other opioid receptors including the delta receptors in the myocardium.
Methadone is highly protein bound (85-90%, mostly to alpha-1-glycoprotein) and has an onset of about 20 minutes after IV administration. Methadone is a long acting drug, but it has a highly variable half-life ranging from 8-150 hours.
Methadone is metabolized by the liver (CYP3A4 and CYP2B6 predominantly). Methadone is metabolized into inactive metabolites which are eliminated via fecal and renal routes. There is no reduction in dosing needed in renal impairment up to stage IV kidney disease. There is no clear guidance in hepatic disease, but dose reduction and increased vigilance/monitoring is recommended.
Methadone has the potential to prolong the QT-interval and may increase the risk of Torsades de Pointes.
Ok so that's methadone. So what specifically makes methadone useful for cardiac surgery Dr. Majewski?
Well there are a few reasons that methadone might be a good choice for cardiac surgery patients. Some of these reasons were elucidated in a randomized, double-blind study by Dr. Glen Murphy and colleagues.
This study randomized patients undergoing CABG, valve surgery, combined CABG/Valves, and ASD repair who were expected to be intubated less than twelve hours into either one group which receive methadone 0.15mg/kg or another group which received fentanyl 12 mcg/kg. They excluded sicker patients such as dialysis dependent patients, patients with LFTS > 2x normal, low EF <30%, patients on home oxygen, or patients that had pre-op IABP, inotropes or emergency surgeries. They also excluded patients taking pre-op opioids or history of opioid abuse.
Post-operative pain was managed with standardized titration of morphine and transitioned to oral acetaminophen-hydrocodone when able to take oral medications. Pain was assessed from 15 minutes to 72 hours post-extubation.
The results of this study showed that the use of intraoperative methadone reduced the postoperative morphine requirements, improved pain scores and improved patient-perceived quality of pain management.
So this study showed overall improved pain control. But was there any increase in complications, or prolonged intubation times?
Actually no, there was no significant difference in opioid related adverse outcomes or respiratory complications. There was also no difference in time to extubation, hospital length of stay, or ICU discharge.
Okay so methadone can improve short term pain and reduce opioid requirements without prolonging recovery, but what about long term outcomes?
Good question. There was a follow up study published by that same group that looked at the use of methadone 0.3 mg/kg of methadone v 12 mcg/kg of fentanyl intraoperatively and used a pain questionnaire assessing the weekly frequency and intensity of pain at 1, 3, 6 and 12 months after surgery. The results showed that patients who were randomized to receive methadone reported a lower frequency of postsurgical pain at 1 month compared to the fentanyl cohort. The methadone group had a median incidence of 0 times per week while the fentanyl group frequency was twice per week. The pain intensity at one month was also lower in the methadone cohort compared to the fentanyl group. After the one month interval pain frequency was less than once per week in both groups.
One thing I would like to point out is the difference in doses between these two studies. The exact dose of methadone that provides adequate postoperative analgesia without significant respiratory depression has not been clearly defined in the literature. In a Review published again by Dr. Murphy In Anesthesiology addressing what is the optimal methadone dose, the authors note that there are few studies measuring the dose response curve to methadone administration, but suggest that more painful surgeries, i.e median sternotomy, require higher doses of methadone.
In a randomized, double-blinded control study of patients undergoing CABG published by Dr. Carvalho, the investigators showed a small improvement in pain scores with a dose of 0.1mg/kg of methadone if given postoperatively compared to morphine. Their study showed that the methadone group showed a mean score of 1.9 ± 2.2 according to the numerical pain scale at 24 h after surgery, whereas the morphine group showed a mean score of 2.9 ± 2.6 (p = 0.029). The authors however note that their results showed a shorter duration of analgesia when compared to a randomized double-blinded study where Dr. Udelsmann and colleagues demonstrated by a longer time to first patient requested analgesia post-operatively with a single 20mg IV methadone dose.
Okay, so a safe and effective dose range is 0.1mg/kg- 0.3mg/kg, but we should always keep in mind other factors when choosing a dose of methadone. Those factors being patient related factors such as age, opioid tolerance, and liver function. Surgical factors that should be considered include the length of surgical procedure and expected amount of pain from the procedure.
In summary, methadone has shown to be effective in reducing opioid requirements post-operatively in a wide range of cardiac surgery patients, with improved subjective pain scores in both the acute setting and at one month with no evidence of increased opioid related adverse events. To me it sounds like a good option in the appropriate setting, keeping in mind the risk of QT-prolongation in select patient populations.
That sounds like an accurate summary to me. One other really quirky finding in the original study was the trend toward more arrhythmias in the methadone group. This is likely due to using less fentanyl, which has some efficacy at reducing arrhythmias, rather than an effect of the methadone in causing arrhythmias.
So now that we have covered methadone let's move on to our next topic which is ketamine.
As a review, ketamine is a NMDA non-competitive antagonist which acts in excitatory neural pathway transmission. Ketamine is a racemic mixture of 2 enantiomers that have similar pharmacodynamic properties with the S+ enantiomer having greater potency. Ketamine is water soluble with rapid onset of about 30 seconds after IV administration. Ketamine has limited protein binding and an elimination half-life of approximately 2-4 hours.
Ketamine also binds to opioid receptors, has central muscarinic receptor analgesic effects as well as sodium and calcium channel inhibition, similar to local anesthetics and gabapentin.
Ketamine is metabolized by the liver cytochrome system (primarily CYP 3A4, CYP2B6, and CYP2C9). Ketamine is metabolized into norketamine, which is an active metabolite. Metabolites are renally excreted, so patients with renal insufficiency may experience prolonged duration of action or increased effects.
Ketamine has effects on multiple organ systems which include cardiovascular effects mediated via inhibition of catecholamine uptake and sympathetic stimulation. These effects may benefit patients with reduced ventricular function. Despite studies having shown direct myocardial depressant effects, at clinically relevant doses ketamine exhibits positive inotropic effects and can produce vasoconstriction via inhibition of endothelial nitric oxide production. The increase in cardiac output in patients receiving ketamine is mainly from catecholamine potentiation. In patients that are catecholamine depleted, ketamine can cause myocardial depression and critically ill patients experience more significant reductions of MAP, SVR, CO and ventricular function.
Ketamine typically induces tachycardia, emergence delirium and dissociative psychotropic effects in a dose dependent manner. Respiratory effects include bronchodilation via beta-2 agonist activity and histamine antagonism while preserving respiratory drive with little to no change in lung volumes
Neurologic responses include increases in CMRO2 and cerebral blood flow, enhancement of SSEP signals, and no change or increases in the bispectral index. There is potential risk of elevated ICP, however in patients that are mechanically ventilated and PaCO2 controlled, CBF and ICP have not been shown to increase significantly in the setting ketamine.
Okay so that's ketamine in general, so now let's talk more about ketamine in regards to cardiac ERAS.
I know Ketamine has been shown in multiple studies and meta-analyses to reduce opioid consumption, reduce analgesic requirements, and improve pain scores, but these studies were in non-cardiac patient populations.
Correct. There also appears to be a wide variation in the opioid sparing effect among different procedures and different patient populations with more of the opioid sparing effect in procedures we typically associate with more pain, such as orthopedic and spine surgery and laparotomy.
So what is the evidence in cardiac surgery?
The literature seems to support that pre-incision ketamine and intraoperative infusion leads to reduced opioid consumption compared to placebo. Lahtinen and colleagues showed in a randomized controlled trial that pre-incision ketamine leads to a longer duration before first requested opioid with no difference in pain scores.
A systematic literature review of ketamine in cardiac surgery published in Annals of Cardiac Anesthesia found the following in patients receiving ketamine:
1) Lower levels of IL-6, IL-8, IL-10, and C-reactive protein at induction and prior to CPB in valve replacement and CABG
2) No reduction in inflammatory markers compared to placebo in off-pump CABG with induction ketamine v. placebo
3) Increased post CPB SVR and MAP
4) Improved postoperative cognition/less delirium in mixed cardiac cases
5) Improved patient pain satisfaction, no difference in pain scores, and less opioid use in CABG surgery
6) Reduced inotrope requirements, earlier extubation, and a lower incidence of MI in CABG surgery
7) Reduced postoperative troponin levels in ketamine/dexmedetomidine vs. sevoflurane/sufentanil group in CABG surgery
a) Another study showed no difference in troponin level or major cardiac events
8) More stable hemodynamics with ketamine 2 mg/kg at induction compared to propofol 0.5 mg/kg with standardized midazolam, fentanyl and rocuronium doses in CABG surgery
9) Ketamine at induction did not improve post CPB oxygenation or reduce ventilator days in CABG surgery
10) No difference in post-operative quantitative EEG in mixed cardiac cases
11) Fewer ventricular arrhythmias in ICU post CABG surgery
12) Less neutrophil superoxide generation from neutrophils in CABG surgery
13) Improved ICU pain satisfaction and recovery in mixed cardiac cases
14) Decreased incidence of shivering and PONV when administered in the ICU
So as summarized in this systematic review, Ketamine is a tool that can provide stable hemodynamics during induction in patients with poor ventricular function. It may induce tachycardia that can be detrimental in patients with coronary artery disease or valvular stenosis. Ketamine can attenuate the body's inflammatory response and reduce cytokine production but the clinical impact of these reductions is unclear. Ketamine can provide excellent post-operative pain relief, leading to less opioid usage and opioid related side-effects, but future studies are needed to draw further conclusions.
That sounds about right to me.
So what's our next ERAS topic?
Up next we have regional anesthesia techniques in cardiac surgery. We will specifically focus on the following blocks:
erector spinae plane
paravertebral
chest wall plane blocks (PECS and serratus anterior)
Parasternal blocks (including both the transverse thoracics muscle plane block, or TTMP for short, and pecto-intercostal fascial plane block, often referred to as PIFB)
Regional techniques have become more and more common in the cardiac realm in an attempt to limit opioid usage and the associated adverse effects from opioids, to improve acute pain control, to limit chronic pain syndromes, and facilitate a timely extubation and ICU discharge, all in an effort to improve the patient's ability to participate in early rehabilitation.
Correct. Ideally the goal is to have a peripheral nerve block that is relatively quick and easy to perform, provides adequate pain control and with limited hemodynamic changes related to the block and few if any side effects.
Okay so I have heard about institutions that perform erector spinae plane blocks for cardiac cases and I think most of the literature supports the efficacy of this block so lets cover that first.
For review, the erector spinae plane block is a fascial plane block that involves injection of local anesthetic deep to the erector spinae muscle group which includes the iliocostalis, longissimuss and spinalis muscles. These muscle groups run sacral to cranial bilaterally between the spinous and transverse processes and extend laterally to the ribs.
Literature that includes imaging and dye studies has demonstrated local anesthetic spread from a single injection is significant, and as such a single injection performed at the T5-T6 level is sufficient for any thoracic surgery. At this level, the trapezius, rhomboid major and erector spinae group itself are all identifiable as three distinct layers in that order medial to the scapula and superficial to the transverse process
We inject approximately 20-30 mL of Local anesthetic deep to the erector spinae muscle group and spread should be visualized deep to erector spinae and superficial to the transverse process
The mechanism of blockade is still not fully elucidated but some studies have shown the potential mechanisms to be from fascial plane spread to the posterior rami of spinal nerves as they branch out from the paravertebral space as well as some diffusion to the anterior paravertebral space itself and ventral rami. Also MRI imaging on cadavers after injection have shown ESP plane block spread into the epidural space and neural foramen as well as along intercostal nerves which may help with additional analgesia and median sternotomy coverage. Some have called ESP a paravertebral by proxy or a “superficial paravertebral” block.
Okay so now what does the literature show for the use of ESP blocks?
Well, in one randomized control trial published by Krishna and colleagues that contained 106 patients comparing ESP vs. Acetaminophen and tramadol, the erector spinae group had significantly lower pain scores with a significantly higher duration of analgesia and showed that the erector spinae group was extubated sooner, tolerated a diet sooner and was discharged from the ICU sooner. The inclusion criteria included elective cardiac surgery utilizing cardiopulmonary bypass.
Okay so that all sounds great! What's the catch?
Well there are risks that are associated with any peripheral nerve block like hematoma, LAST, infection, and bleeding. Unique to the erector spinae nerve block is accidental intrapleural injection, although with the use of ultrasound and given that anatomical target is superficial to the transverse process, the risk of pleural injection/penetration is much lower than if a traditional paravertebral were attempted.
In general, the ESP block is the swiss army knife for procedures anywhere on the thorax. Minimal hemodynamic consequence is expected, and it can even be safely performed in a coagulopathic or anticoagulated patient. For cardiac surgery it can be done pre or post procedure, is amenable to catheter placement, and is well away from the surgical field making it an ideal block. Really the only drawback is it cannot be performed in a supine patient.
You mentioned it is safe in coagulopathic patients. What about bleeding risk and anticoagulation given the nature of cardiac surgery?
The American Society of Regional Anesthesia has not yet officially classified ESP blocks as superficial or deep in regards to compressibility but most practitioners feel that it falls into the superficial classification given it could likely be compressed and hematoma would be unlikely to cause devastating neurological problems unlike neuraxial blocks.
Okay so no catch?
Well the only catch is that this is a relatively new block for which there are limited studies and data regarding the efficacy and safety of the block, and the one RCT had some methodological issues in regards to blinding, concealment and lack of sham blockade.
Sounds like the evidence is promising but not yet conclusive and more studies are needed before it becomes a routine recommendation.
Let’s now move on to some of the other nerve blocks. If the ESP is a paravertebral by proxy, what are the differences between ESP and performing a paravertebral block?
Well, a paravertebral block is done by injecting local anesthetic alongside specific vertebral segments in proximity to the exit of spinal nerves deep to the costotransverse ligament, typically via a loss of resistance or ultrasound guided technique. The paravertebral space boundaries are the parietal pleura anterolaterally, vertebral body and intervertebral disc medially, and the transverse process and superior costotransverse ligament posteriorly.
Within the paravertebral space runs the intercostal nerve, the dorsal ramus, and intercostal vessels. The space communicates medially and laterally with the epidural space and intercostal spaces respectively, and can communicate with the contralateral paravertebral space through the epidural space which may allow spread of local anesthetic cranially and caudally but the amount of cranial-caudal spread has been shown to vary widely between patients and depend on approach and technique.
The mechanism of blockade appears to be from blockade of somatic and sympathetic nerves as they exit the foramen into the paravertebral space with spread laterally into the intercostal space. There is the potential for spread proximally into the epidural space, and epidural blockade has been described in the literature.
So given that there is spread within the epidural space itself does this produce the same effect that we see with epidural injection?
Actually, no. The epidural spread via paravertebral blockade is quite variable and limited. The literature has shown that when comparing epidural to PVB, patients who receive PVB have less urinary retention, less vomiting, shorter ICU stay duration and is as effective in relieving post cardiac surgical pain as published by El Shora and colleagues.
So if PVB is superior to TE in that it has similar analgesic properties but less hemodynamic compromise, why wouldn't you always choose a paravertebral block instead of ESP?
Well there are 2 reasons mainly. One reason is risk of complications. Despite the advancement of ultrasound guided technique, a paravertebral block is technically more difficult to perform. The closer proximity to the lung pleura increases the risk of pleural puncture and pneumothorax. The paravertebral space is also in closer proximity to the intrathecal space increasing the risk of epidural injection. Another potential risk is hematoma formation and potential epidural hematoma with neurologic compromise. ASRA and many providers consider a paravertebral to be a deep block and recommend neuraxial anticoagulation precautions, including avoidance in all coagulopathy, holding heparin at least 60 minutes after the block placement, and delaying of the case in the event of a traumatic placement.
Second is the ease (or lack thereof) of placement. Since paravertebral spread medially along the epidural space and laterally intercostally is unpredictable with large volume injection practitioners typically opt for injection at multiple levels to provide full coverage. Given cardiac surgery and pain coverage needs for median sternotomy, reliable adequate coverage would require multiple injections bilaterally which can be difficult and time consuming, as well as amplifying the opportunity for complications.. Hence why this block is more typically indicated for unilateral procedures or analgesia as an alternative to TE.
Not to mention the practical difficulty trying to perform this at the end of a case while a patient is still intubated and sedated.
Yes it is quite challenging at times.
What about placing a paravertebral catheter?
Paravertebral catheter insertion prior to blockade might be a potential option keeping in mind the aforementioned risks and benefits. A meta-analysis published by A. Scarfe in the European Journal of Cardiothoracic Surgery looked at 22 RCT’s showed continuous PVB provided equivalent pain control to epidural with less nausea, hypotension and urinary retention. However, given the limited number of studies with a relatively small sample size, adverse events may potentially be underestimated so it is hard to recommend paravertebral blockade over other options.
Alright well with that, let's talk about the other options that are available.
So the PECS blocks are becoming pretty popular. I actually just did 4 last week in our outpatient center for some breast surgery cases. The PECS I and PECS II blocks are relatively new blocks that have shown some promising application in cardiac surgery. The PECS block was the product of trying to devise a block that would anesthetize the medial and lateral pectoral nerves that provide innervation to the pectoralis muscles.
To perform a PECS I block, ultrasound guidance is used to inject local anesthetic into the fascial plane between the pectoralis major and pectoralis minor muscle. This will provide analgesia from T2-T6 on the anterior and lateral chest wall.
The PECS II block includes an additional injection, lateral and slightly inferior to the site of the PECS I, at the fascial plane formed between the serratus anterior and pectoralis minor. This is thought to provide additional blockade of the upper intercostal nerves and provide better axillary coverage. The main drawback form performing PECS blocks is in general they are less reliable at blocking the parasternal area. Extensive studies involving breast surgery have shown to spare this space, making it less attractive for median sternotomy. They also lack the potential for pleural analgesia that the previously mentioned blocks afford as they target the lateral cutaneous branch of the ventral ramus. The serratus anterior plane is also a great block for chest wall and a single injection can provide analgesia on the hemothorax from T2-T9, but also is limited in its ability to provide analgesia in the parasternal space and has limited efficacy for alleviating pleurisy from chest tubes.
Parasternal blocks (TTMP and PIFB) are also options and both would provide excellent analgesia to the sternum and have been shown to reduce opioid consumption post cardiac surgery, reduced pulmonary complications, and reduced incidence of chronic post-sternotomy pain.
Parasternal fascial plane blocks however do have the drawback of potential complications when performed preprocedure (LIMA bed is within the plane of injection for the TTMP) and vascular injury could have serious surgical implications. Injection post procedure would mitigate the risk of hitting the LIMA with a block needle, but post-surgical tissue plane disruption postoperatively limits drug spread and analgesic efficacy. These blocks also do not provide analgesia for chest tube pain, which is often a common post-operative complaint. These are the reasons why we choose ESP blocks in the heart rooms at our institution.
Good synopsis. I think overall the erector spinae plane block seems to provide the best balance of efficacy, utility, and safety, but there is a lot of ongoing investigation and new data should give us more direction in the future.
Alright, so our next topic is something that is becoming more common in the cardiac anesthesia world, but not something we do often here at our institution, which is intra-op extubation.
According to data collected by the Society of Thoracic Surgeons and compiled in their performance measures, prolonged intubation/ventilation is defined as patients who require intubation for greater than 24 hours. Early extubation is defined as extubation within 6 hours.
It is this 6 hour mark that we use at our institution for our “fast track” criteria and goal. The 6 hour time mark itself is a rather arbitrary goal, with little to no evidence supporting saying 5 hours is better than 6, or that worse outcomes will occur at the 7 hour mark.
There is, however, strong evidence supported by a meta-analysis by He that showed prolonged ventilation after 48 hours increases the risk of ventilator associated pneumonia from 6.37% to 35.2%. Altogether, we know that prolonged intubation has been shown to increase morbidity.
In a study performed using the STS metric data performed by Crawford and colleagues and published in Seminars in Thoracic and Cardiovascular Surgery found that major morbidity, prolonged length of hospitalization, and mortality did not significantly increase until patients were intubated for more than 12 hours after surgery.
A more recent study by Richey and colleagues published in the Journal of Cardiothoracic and Vascular Anesthesia has shifted the paradigm somewhat because this study showed that a multidisciplinary extubation protocol reduced median time to extubation after elective cardiac surgery from 7.4 hours to 5.7 hours, but showed increased ICU length of stay and worsened renal outcomes in patients that were extubated within 6 hours.
This seems to indicate that although a standardized protocol for extubation might hasten time to extubation, individual patient factors should be weighed and regular evaluation of the appropriateness of extubation should be sought instead of a standardized metric for all patients. There is also some push in the cardiac community to move away from the 6 hour extubation as a quality metric altogether and to look at the time to extubation more as a predictor of outcome as published by Dr. Goeddel and colleagues also in the Journal of Cardiothoracic and Vascular Anesthesia.
Yes I think it is important to recognize how individual patient factors may affect the timeline to extubation and that a universal quality metric may incentivize institutions to extubate at a certain time but not actually improve outcomes.
Okay so that’s mostly talking about early extubation or “Fast Track” as we call it. Now let's focus our last couple of minutes on intra-operative extubation.
There has been more recent investigation into intra-operative extubation and a study published by Badhwar and associates that compared intra-operative extubation to extubation at less than 6 hours and less than 12 hours showed that patients extubated in the OR had a significant reduction in ICU length of stay, reduced hospital length of stay, and conferred significant cost reductions. There were no significant differences in re-intubation rates. There was also significant improvement in the frequency of direct to home discharge in the intraoperatively extubated patients compared to the 6 and 12 hour groups.
Ok but obviously there are only certain patients that should be extubated in the OR. Are there any predictors of successful extubation?
Yes! one study published by Subramaniam and colleagues showed there were some independently associated factors with successful OR extubation. Positive prognostic criteria included younger age, lower BMI, higher pre-op serum albumin, the absence of chronic lung disease and diabetes, a less-invasive surgical approach, isolated CABG, elective surgery, and lower dosage of intraoperative fentanyl all were associated with a higher success rate of intraoperative extubation.
This group also developed and validated a scoring system where a score of <0 suggested extremely low probability of successful intraoperative extubation, scores of between 0 and 5 correspond to possible successful OR extubation but clinician judgment should guide the decision, and scores 6 and above corresponded with high probability for successful intraoperative extubation after any adult cardiac surgery.
So I think what we can take from this information is that there is strong and growing evidence that early extubation can improve patient outcomes and patient satisfaction while also reducing resource utilization in select patients, but to do so requires a multidisciplinary approach in close coordination with surgeons, anesthesiologist, nurses and ICU staff. Clinical judgment must also be used as early extubation does not lead to improved outcomes in everyone.
Yes I think intraoperative extubation is something that will continue to become more and more commonplace as more data comes out that shows the safety and improved outcomes that is expected with its use.
That is all the time that we have today, but thank you for listening and I hope this information helps with some of your clinical questions or maybe drives you to answer some of the questions that we still don't yet have answers for.
Thanks for joining me Dr. Majewski.
The pleasure was all mine, Dr. Bolyard.
