We discuss the medications typically used after organ transplant, their impact on critical illness, and how to manage them when these patients show up sick—with Olivia Philippart, transplant clinical pharmacist specializing in liver and kidney transplant at University of Kentucky HealthCare.
Most kidney transplants will end up on a calcineurin inhibitor like tacrolimus (or the older cyclosporine), an anti-proliferative like mycophenolate mofetil (Cellcept) or the older azathioprine, and possibly corticosteroids (e.g. prednisone). Formulations for some of these may need to be adjusted based on your formulary, so consult your pharmacist to get the equipotent dose.
How these patients present, their degree of immunosuppression, and risk of rejection, are all heavily dependent on the time since transplant. A patient <6 weeks from transplant is high risk for nosocomial infections (e.g. post-op complications). A patient years out is mainly at risk of the same infections as anybody else, in addition to opportunistic infections related to their immunosuppression.
Latent viral infections unmasked by immunosuppression or acquired from the transplant are usually not a surprise, as these are tested for as part of the initial workup.
The highest risk of organ rejection and hence the highest degree of immunosuppression is in organs with substantial amounts of lymphoid tissue transplanted. The highest is small bowel, then lung, then heart/kidney/pancreas, then the least in liver (liver transplant can actually overall support immune function). Some livers can be maintained on monotherapy, while lungs usually need triple therapy, and often dual therapy is used in the middle category.
Durations of therapy for identified infections may be longer in the immunosuppressed than for routine ICU care.
Mycophenolate is the first agent to consider dose reducing or holding in the setting of active bacterial infection. How to handle this depends on the severity of infection and degree of concern for rejection.
Both our calcineurin inhibitors (tacrolimus and cyclosporine) are primarily cleared in the liver and gut, so when there is liver impairment or bowel problems, dose decreases are often needed. Dietary intake also reduces drug absorption whereas NPO status may increase it. These drugs are heavily protein bound so albumin fluctuations (e.g. from malnutrition) may impact free levels.
Drug interactions are common as well; CYP3A4 or PGP inhibitors like diltiazem or verapamil, azole antifungals, amiodarone, macrolides (although not azithromycin), and paxlovid will tend to increase levels, while inducers like phenytoin or phenobarbital will tend to decrease them.
Overall, the therapeutic index of the calcineurin inhibitors is small, so have a low threshold for checking trough levels early and often.
After holding a dose, the serum levels will normalize within 3-5 half-lifes, but full return of immune function may take several weeks. However, the baseline level of immunosuppression is usually not so profound that the difference between “off” and “on” is huge and binary.
Organ rejection is possible but rare when drugs are acutely held (for days, maybe a week or two) in setting of severe infection, as this is already a relatively immunosuppressed state. However, this depends heavily on the time from transplant, and the organ transplanted.
Mycophenolate levels (or mercaptopurine levels for the older azathioprine) tend not to fluctuate as much; the metabolism (via glucuronidation) is not as sensitive to hepatic function, so monitoring levels is rarely needed.
Most of our immunosuppressants are not significantly renally cleared, so renal injury (even dialysis) usually require no dose adjustment. However, they can be nephrotoxic, so high levels may CAUSE renal injury, not vice versa.
Tacrolimus is available in either immediate release capsule (taken twice daily) or a long-acting form (taken once daily). The latter helps to decrease peaks and some of the neurotoxicity (seizure, tremors), but cannot be opened. There is an 80% conversion between formulations (multiply the long-acting dose by 1.2, then divide by half to get the short-acting BID equivalent). Levels checked should always be troughs.
Short-acting tacrolimus capsules should not be opened and put down tubes, but can be opened and given sublingually (50% dose reduction)—just dribbled under the tongue—although nurses need to take special precautions like gowning and double gloving. There is also a liquid tacrolimus formulation available.
IV tacro exists, but has substantially higher nephrotoxicity, and the dose conversion is tricky; other routes are preferred.
Cyclosporine is available in suspension which can go down a feeding tube, or via IV form (dose reduction needed).
IV mycophenolate is available (1:1 conversion), as well as a liquid suspension.
Steroids can be used in the ICU as usual (e.g. stress dosing), and indeed temporarily converting transplant patients to a pure steroid regimen is a reasonable approach during critical illness (remember: 20 mg hydrocortisone is equivalent to 5 mg prednisone).
It’s generally sound to touch base with someone who knows a patient’s transplant history, even years out (often just their normal nephrologist, pulmonologist, etc in that case, not necessarily the original transplant team), when these patients are admitted for critical illness.
Calcineurin inhibitors can cause headaches, seizures, even PRES, hyperkalemia and hypomagnesemia, and hypertension, hypercholesterolemia, hyperglycemia/diabetes. Attributing these effects to the drug is usually a diagnosis of exclusion.
We discuss assessing patients prior to intubation or other airway management, including both elective and emergent circumstances, with Dr. Jed Wolpaw, anesthesiologist and intensivist from Johns Hopkins, anesthesiology residency program director, and host of the ACCRAC podcast.
Edentulous (toothless) patients are usually easier to intubate, but harder to mask ventilate. Heavy beards are harder to mask (can you trim it, or cover it with a Tegaderm?), larger neck circumferences, and larger tongues likewise.
Consider the history, particularly involving the head and neck anatomy. Is there surgical history here? Jaw or oral surgery? Prior trachs or oral/neck radiation? Rheumatoid arthritis or Down syndrome (which can cause atlanto-occipital instability and may warrant trying to limit any forced neck extension)?
Start by looking into the patient’s mouth (mouth open, sitting up, no “aah”):
Mallampati score (do you see the entire uvula, part of it, soft palate, or hard palate only?)
How is the dentition? Remove dentures if present. Are there loose teeth?
Is there an excess of soft tissue in the mouth (large tongue, etc)?
Evaluate the thyromental distance (thyroid bump to chin); <3 cm (or fingerwidths) suggests a more “anterior” airway.
Evaluate neck flexion and extension (passively if necessary) to appreciate limitations in neck mobility.
If the patient is able, evaluate how well the jaw can protrude/prognath: ability to bite more of the upper lip with the lower teeth is a good thing. This is probably the single most predictive test for airway difficult, although it usually requires patient cooperation.
Review the chart (or ask the patient) for prior documentation of intubation or anesthesia to determine if they have a history of a difficult airway. This can require some interpretation of the context and who was intubating previously. Good practice when documenting: write exactly what you did, and if it was difficult, write why! If you used a technique like awake intubation, a bougie, etc for elective or training reasons, document that reason so they don’t earn a label of a difficult airway forever.
The STOP-BANG score is used to predict post-anesthesia airway obstruction (i.e. OSA), and probably has some association with faster deoxygenation and difficult mask ventilation, but is generally not super relevant for intubation.
A patient with any concern for difficult intubation warrants consideration for factors also contributing to difficult LMA placement or cricothyrotomy. LMAs are difficult to place when the mouth opening is very small (about 2 inches) or the oral-laryngeal anatomy is unusual, and crics are difficult when the neck anatomy is impossible (eg a superimposed tumor, goiter, or heavily distorted anatomy). A patient who cannot have a cric may warrant an awake intubation to avoid the risk of inducing a patient who cannot be rescued.
Obesity is not a predictor of anatomically difficult intubation. Mask ventilation may be a little harder if there is increased oropharyngeal soft tissue. It is a predictor of physiologic difficulty (faster desat), though.
For emergent intubations: confirm code status, briefly evaluate the head/neck/mouth, use video laryngoscopy. Use hemodynamically stable agents for induction and reduce the dose, and ensure the team knows to subsequently sedate any patient who received a long-acting paralytic. Have a vasopressor drip ready, or better yet, running. Always set up everything and be prepared for every eventuality before you take away a patient’s ability to breathe.
Either RSI with paralytics, or perform awake intubation. Otherwise, never RSI the critically ill without neuromuscular blockade, which will reliably reduce your chances of success. Short-acting paralytics (succinylcholine) are brief—i.e. not much longer than the apneic period of a short-acting sedative—and long-acting paralytics (eg rocuronium) can be reversed with suggamedex, in the rare situations where letting the patient wake up and resume breathing is a smart move.
The one exception might be a ketamine-only intubation, which generally keeps the patient breathing, allowing you to either proceed to paralyzing or not depending on what you see, or maybe allow them to wake up.
While it’s nice if an emergent intubation has been NPO, it probably won’t change your technique; changes in gut motility in the critically ill mean almost anybody can have stomach contents. Treat most ICU patients as if they have a full stomach, i.e. RSI. The one exception: the PREVENT trial showed that mask ventilation during induction (usually a no-no for RSI) of critically ill patients does not increase aspiration risk and does reduce hypoxemia, so should probably usually be done.
In the highest aspiration risk patients like SBO or upper GI bleeding, keep the head of bed elevated, ensure ample/multiple suctions catheters, and be ready/willing to intubate the esophagus intentionally with your ETT and place it to suction to divert the stomach contents while you use a fresh ETT to intubate the glottis. Placing an NG beforehand to decompress the stomach is hit or miss as it can induce vomiting; it works better in a fully awake patient (who can manage any vomiting).
We should probably still learn and teach direct laryngoscopy, but do so using a video scope with regular-geometry blade.
Bedside nurses and providers (physicians, PAs, NPs) tend to see the world differently, much of it driven by their training and the systems they work within. We chat about reconciling this and how to best function as a team.
We discuss head and neck surgery with Dr. Alexandra Kejner, otolaryngologist at the Medical University of South Carolina specializing in transoral robotic surgery, reconstructive surgery including microvascular free tissue transfer, salivary neoplasms, and sialoendoscopic procedures.
Robotics has enabled much less invasive approaches to many head and neck procedures.
Major airway procedures create edema, and there is always risk for bleeding, so patients often remain intubated overnight.
The other common ICU indication is a free flap, a portion of tissue (potentially including skin, subcutaneous tissue, muscle, even bone) removed from a remote site and transplanted into the head and neck area, with vessels anastomosed. These are at risk of failure and require close monitoring.
Most of these procedures will involve placing a tracheostomy, and potentially a PEG (or NG). This facilitates both surgical access and early recovery.
Tumors are superficially resected with adequate margins, then reconstruction begins. Meanwhile, exposure of deeper structures and deeper resection occur, which may involve a jig to guide the removal (prepared in advance from imaging), and a matching cut to prepare the flap tissue. Lymph nodes are removed en bloc. Then the flap is transplanted and vessels anastomosed (at least one robust artery and vein), using microsurgery and teeny sutures (often 8-0 nylon).
As a supplement to the clinical exam, an implantable Doppler monitor is occasionally left in place to augment post-op monitoring of perfusion, as well as sometimes a Vioptix near-infrared spectroscopy device which performs real-time tissue oximetry.
On POD 0-1, hourly nursing monitoring of the flap is usually needed, with periodic provider checks. Changes in the exam (swelling, turgor, cap refill, color), signal, or bleeding may require return to the OR for revision. A single ICU night is the norm, although comorbidities are common and may require a longer stay if the stress of surgery unmasks other problems.
Laryngectomy may be performed, involving removal of the larynx (voice box), leaving a blind pouch; the lungs no longer connect to the upper airway in this case, and the entire team should be aware of this anatomy, as the patient cannot be intubated or their airway otherwise managed from above.
Most flaps will be on a baby aspirin and enoxaparin, but occasionally may use a heparin drip.
Most will receive three doses of dexamethasone, both to reduce edema and to treat any adrenal insufficiency.
Chlorhexadine or salt water oral rinses are performed to keep the operative site clean.
Multimodal pain management is needed for both the oral site and the donor flap site.
A drop in the Vioptix signal from the initial post-op reader, neck swelling, or difficulty breathing (dyspnea, hypoxia, etc) all warrant immediate involvement of the surgical team for danger to the airway or the flap. Flaps might also turn purple from venous congestion, sometimes a little later, also a surgical emergency.
A questioned flap might be scratched to see if it bleeds (which is good).
A patient in shock might need vasopressors, fluid, or to be hypotensive, none of which are great for a flap. A balanced approach is probably best. A low-dose phenylephrine drip may be the most appealing pressor, and vasopressin might be the riskiest. MAP >65 is a minimum, some prefer higher (>80).
Intro-operative feeding has been used in some centers due to the prolonged procedure times.
Flap failure historically was most often from a venous clot, but this has reduced over time; nowadays it’s often late failures due to a salivary fistula contaminating the area and creating a region of digestion, clot, and breakdown.
Surgeons will occasionally request deeper sedation (or even forcing the patient to maintain a specific neck position) to avoid dislodging monitors, disrupting a very delicate anastomosis, etc.
A swollen or firm anterior tongue, ooziness in the mouth, or a difficult airway on the initial intubation may lead a surgeon to request delaying extubation.
The immediate post-op appearance usually heals into a better eventual aesthetic result. Occasionally measures like prosthetics can be used.