Miller St. Louis University School of Medicine 2018 – Right Heart Catheter Waveforms


  • RA 1-5 mmHg
  • RV 25/5 mmHg
  • PA 20/10 mmHg
  • LA 3-12 mmHg (PCWP estimates the LA pressure)
  • LV 120/12 mmHg

Screen Shot 2020-04-01 at 20.01.25


Negative inspiratory efforts -> Use end-expiratory pressure in respiratory cycle to estimate R heart pressures

Screen Shot 2020-04-01 at 20.36.08.png

  • end-expiratory pressure most closely resembles atmospheric pressure with negative pressure breathing
  • though you may be tempted to say that beginning of inspiration closely resembles atmospheric pressure–this is true, but the expiratory phase is naturally much longer/easier to catch than beginning of inspiration

Positive pressure/mechanical ventilation -> Use opposite approach compared to neg inspiratory efforts; use end-inspiratory pressure

Screen Shot 2020-04-01 at 20.37.10.png

  • inspiratory phase will increase the thoracic pressure and impair venous filling and impair venous return
  • use end-inspiratory pressure in mechanically ventilated patient (? not sure why this is; seems like an error)


Screen Shot 2020-04-01 at 20.37.29.png

  • a-wave -> follows P wave on rhythm strip by 80 ms
    • pressure increase from atrial contraction
    • “atrial kick” of final bolus pumped into the RV prior to RV systole
  • v-wave -> passive venous filling of atria from/after ventricular systole
    • corresponds to t-wave from rhythm strip
  • c-wave -> sometimes seen; tricuspid annulus towards the RA at onset of ventricular systole
  • x-descent -> atrial relaxation; downward motion of AV junction
  • y-descent -> rapid emptying of the RA after the TV opens

*anecdotally, we use the term “c-v wave”/combine the c-wave and v-wave on the pressure waveforms in practice to more easily compare them to the EKG lead–i.e. treat c-wave and v-wave as one entity.



Screen Shot 2020-04-01 at 20.38.27.png

  • this picture chose R heart cath waves at the peak, but definitely staying away from the valleys
  • a-wave -> identified by drawing line down from the P-wave
  • v-wave -> identified by drawing line down from the T-wave


Screen Shot 2020-04-01 at 20.39.27.png

  • delay in the RV wave systole from the EKG QRS wave reflects the delay in pressure wave traveling thru the pulmonary circulation 110 cm PA catheter
  • RV diastole pressure wave is flat/low slope to reflect the RV compliance/ability to stretch
    • “black circle” above is the RV diastole
    • “green arrow” is where likely location of a-wave would be


Screen Shot 2020-04-01 at 20.40.02.png

  • systolic pressure -> from the wave that just follows the peaked waveform (i.e. this is the end-expiratory wave)
    • if you picked the highest wave, then exhalation is still occurring; thus, pick just one after the peak
  • diastolic pressure -> the valley preceding the systole that you just chose


Screen Shot 2020-04-01 at 20.40.47.png

  • diastolic step-up clearly seen on PA compared to RV waveform
  • RV systole still remains same as PA systole
  • “green arrow” -> closure of the pulmonic valve which is on the descent side of the PA systolic wave
  • peak pulmonary artery pressure occurs within the T-wave on EKG

Screen Shot 2020-04-01 at 20.41.57.png

  • end-expiratory waveform for the PA wave
    • choose the systole from wave right after the peak (i.e. since peak wave will be during when exhalation is still occurring, choose the one right after for end-expiration)
  • again, the peak/systole of the PA waveform occurs during the T-wave on the EKG (just like in the RV waveform)
  • diastolic PA pressure -> choose the valley right before the chosen PA systole (seen as circles in the image below)

Screen Shot 2020-04-01 at 20.42.23.png


  • a-wave -> time delay with a-wave compared to EKG P-wave
    • since pressure has to traverse the pulm capillary bed
    • therefore, the a-wave will be 240 ms following the P-wave on EKG
    • the a-wave will correspond to the end of the QRS complex
  • c-wave is absent on wedge -> LA pressure is transmitted thru the pulmonary capillary bed which dampens the wave by the time reaches the PA catheter
  • PCWP is indicated by a-wave
    • found at the end of the corresponding QRS wave
    • located at end-expiration
    • the machine averages the two a-waves on the image below and reports that as PCWP

Screen Shot 2020-04-01 at 21.59.38.png






Hyzy Chest Physician 2020 – Editorial on neuromuscular blockade/paralysis and PETAL Network trials

Initial studies into neuromuscular blockade were from Light et al. Anesth Analg 1975;54[2]:219 which showed that could be appealing

Then, showed that NMB could avoid excess tachypnea with increasing oxygenation per Hansen-Flaschen et al. JAMA 1991;26:2870

In ARDSNet, the pts were allowed to breathe up to 35/min

  • this prompted the thought that maybe we shouldn’t do that; maybe, NMB could be used; however, at this time, there was still concern regarding neuromuscular weakness as adverse effect

High-frequency oscillatory ventialation

  • two negative trials sidelined this approach
  • Ferguson et al. N Engl J Med 2013;368[9]:795 showed increase in mortality

Start of the modern discussion of NMB early to avoid asynchrony happened with the Forel et al. Crit Care Med 2006;34[11]:2749 which showed that less lung inflammation occurred with NMB

ACURASYS trial then showed that mod/sev ARDS could have mortality benefit with the use of NMB comparable to that seen in low tidal volume trial

  • Papazian et al. N Engl J Med 2010;369:980

PETAL Network then looked into NMB via the ROSE trail

  • this failed to confirm the mortality benefit that Papazian et al. saw in ACURASYS
  • some will cite the heterogeneity of treatment effect as reason for not seeing mortality benefit
  • others will say that there are important design differences between ACURASYS and ROSE
    • ROSE used the high PEEP algorithm to titrate PEEP to FiO2 rather than the conventional low PEEP approach (which was used in ARDSNet and ACURASYS trials)
    • theory: the high PEEP may have mitigated the NMB benefits
    • importantly, there was not a higher incidence of neuromuscular weakness in the NMB group
  • despite the lack of clear mortality benefit in ROSE, NMB is still widely available, inexpensive, and easily performed per Co et al. Crit Care Med 2019

Question remains whether combining NMB and proning is the way to go

  • Goligher et al. Am J Respir Crit Care Med 2014;190[1]:70 found that those pts who are recruitable with PEEP (those whose PaO2 increases w/ increasing PEEP in the face of unchanged or minimally-changing plateau pressure) may also demonstrate a mortality benefit
  • though some clinicians are able to use proning without NMB, many are not able to use without NMB—in fact, NMB was widespread in PROSEVA

Cutler Dana-Farber 2013 – BMT 101 & Lazarus Louisville Lectures 2017 – Allogeneic HCT


  • Elimination and replacement of diseased bone marrow, poorly functioning marrow, immunologically compromised marrow or metabolically compromised marrow
  • Protect against ultra-high doses of chemo
  • Establish immunologic platform


  • conditioning -> preparing the recipient for txp
  • transplant -> day 0
  • engraftment -> waiting period while the marrow takes
  • recovery

DECISION TREE FOR TRANSPLANT -> disease, stage, and patient-specific decision

  • often a risk-benefit analysis taking into account the pt’s age, functional status and ability to tolerate the intervention (i.e. will they be able to tolerate receiving high-dose chemotherapy if auto-HCT? will the transplant appreciably affect their disease prognosis?)
    • age plays a huge role clinically in the prognostication/decision to do HCT; functional status also plays a large role
  • though, HCT is often for the ability to tolerate high-dose chemo or to achieve a graft-vs-tumor effect, there are certain malignancies where cure is not the goal (e.g., myeloma) but rather the goal is to prolong meaningful survival
  • in addition to knowing the specific primary malignancy, the team will often want to know the high-risk features (or specifically markers) of the disease -> often a specific gene mismatch or presence


  • conditioning regimen: high/myeloablative
  • donor type: self, obviously
  • degree of match: perfect (duh, it’s your own cells)
  • source: bone marrow or peripheral blood
  • high doses of chemo and/or radiation designed to kill tumor -> therefore, autoHCT is really just stem cell rescue (not really a transplant); it allows you to use high-dose chemotherapy to wipe out the malignancy before rescuing the patient with the infusion of autoHCT


  • conditioning regimen: high/myeloablative or reduced intensity
  • donor type: related or unrelated
  • degree of match: matched, mismatched, or highly mismatched (i.e. perfect match related donor (MRD) 10/10 HLA; matched unrelated donor (MUD); haploidentical (i.e. counterintuitively, you’re able to use half-matched cells from a family member–as long as you concomitantly infuse cytoxan, it works); mismatched unrelated (mmURD) or umbilical cord blood (UCB)
    • interestingly, the order above is the generally preferred order -> the haploidentical with cytoxan is more preferable than a mismatched unrelated donor even if they’re matching at 9/10 HLA
  • source: bone marrow, peripheral blood, or umbilical cord blood
  • two mechanisms for cure -> 1) immunologic via the graft vs. tumor effect and 2) chemo and/or radiation


a combo of physical and chemical agents prior to stem cell transplant with purpose of reducing tumor burden and (in the case of the alloHCT) to allow engraftment of donor cells.

traditionally, the conditioning regimen was considered myeloablative

Myelosuppression -> physically to make space for the new marrow to reside

Immunosuppression -> to prevent rejection of the graft by the immune system of the recipient

MYELOABLATIVE CONDITIONING -> toxicity is higher but relapse is less -> long-term outcomes the same though (?survival) -> conceptually, you’d love to do a myeloablative everytime–minimize relapse potential and maximize ability for graft to attack tumor; in reality, this is too toxic for many pts

  • total body irradiation: 450 cGy single dose
  • total body irradiation: >/= 800 cGy fractionated +/- cyclophosphamide
  • standard busulfan/cyclophosphamide (“Bu/Cy”)
  • melphalan > 150mg/m^2 +/- other (“high dose melphalan”)-
  • Bu > 9mg/kg +/- other (“high dose busulfan”)

*anything other than the above 5 options is considered reduced intensity or non-myeloablative

NON-MYELOABLATIVE CONDITIONING -> less toxicity but higher relapse -> long-term outcomes the same though (?survival)

Reduced intensity

  • TBI > 200 but < 500 cGy single dose
  • TBI < 800 cGy fractionated +/- other
  • melphalan < 150mg/m^2 +/- other
  • busulfan < 9mg/kg +/- other


  • TBI 200 cGy alone
  • fludarabine + TBI 200
  • fludarabine + cyclophosphamide


Matching the donor/recipient for HLA is the goal (the human leukocyte antigen molecule is the human version of the major histocompatibility complex)

Matching non-HLA loci are important -> not done as of 2013 lecture


Histocompatibility -> analogy is UPC code on cereal box

  • inherited histocompatibility for the HLA
  • sisters/brothers inherit the same possibility for HLA

Minor antigens -> different than major histocompatibility complex

  • they’re minor HLA antigens which aren’t taken into account (?)
  • therefore, the matched sibling donor is ALWAYS better than the “perfectly matched” unrelated donor

Mismatch -> there’s a benefit to mismatch (?) -> the greater the mismatch, the greater the graft vs. tumor effect which offsets the morbidity assoc with the also greater graft vs. host disease effect


Mobilized peripheral blood -> less relapse, but higher chronic GvHD -> has more T cells

  • peripheral blood cells are hooked up to essentially a dialysis machine -> the cells are pheresed off the pt
  • also, better for pt’s with late stage cancer/advanced malignancy <- mobilized blood are activated cells
  • faster neutrophil and plt recovery with mobilized blood
  • less chance of graft failure (can think about this as you’re mobilizing blood from all over the body/it’s more robust than marrow aspiration)
  • req’s 12-15 days to engraft

Bone marrow -> higher relapse rate with bone marrow

  • marrow has higher rate of graft failure (think about this as you’re getting only a small, localized sample wherever you’re aspirating)
  • difficult to collect bone marrow -> ?general anesthesia required for pt
  • req’s 18-21 days to engraft (the period of neutropenia) -> quickest source to engraft

*no difference between peripheral blood and bone marrow with acute GvHD

*no difference between peripheral blood and bone marrow at 5y out -> similar survival, similar relapse

*?is marrow better though? -> marrow recipients have better psychological well being, less burdensome cGvHD (and therefore, less immunosuppressants)

*80% of transplants are still mobilized blood though -> ?should we switch back to marrow?

Umbilical cord blood -> less GvHD risk but higher risk for infectious complications (remember, the baby CD24/stem cells have not seen any antigens)

  • easiest of the stem cells to collect -> stored at time of delivery
  • longest time to engraft (~25d-4w), but highly variable time to engraft
  • has fewest number of T cells and they’re immature -> therefore, the recipients of umbilical cord blood are very immunocompromised
  • therefore, compared to peripheral blood and bone marrow, it is the lowest rates of GvHD
  • better graft vs. tumor effects w/ cord blood
  • b/c it immature from an immunologic standpoint, you can purposely mis-match cord blood
  • therefore, you can use 4 out of 6 matched units <- Cutler et al. uses 4/6 matches routinely w/ cord blood b/c it’s less immunogenic
  • also, if you could find more matched than 4 matches, you can probably find a matched adult donor and can use a matched adult donor instead of cord blood


Treg and Tcon

  • Treg (regulatory T cells) are given on Day 0 while Tcon (or conventional T cells) are given on D +2
  • Treg are taken from the donor and infused into the host where they “teach” the infused HCT to tolerate the host tissues (i.e. avoiding GvHD)
  • this has allowed places like Stanford to test RCTs where pts get alloHCT and then randomized to no GvHD immunosuppressive ppx vs. GvHD immunosuppressive prophylaxis


Checking for relapse or graft failure

Day +90 is ?standard day that check for relapse

  • check BMBx or PET scan
  • minimal residual disease (or, MRD) is saying that there’s no primary malignancy detectable -> at this point you can say CR1 or complete remission #1
    • they say minimal residual disease b/c it uses technological methods that stand in contrast to the traditional methods for determining relapse (i.e. looking at a path slide which is antiquated)

Post-Transplant Lymphoproliferative Disorder (PTLD)

  • B-cell proliferation due to therapeutic immunosuppression after transplant

Graft failure -> results in pan-cytopenia and high risk for infection or bleeding complications

  • could be reversed w/ additional donor cells (?kind of like a do-it-again approach?) -> donor lymphocyte infusion (?)
  • the major supportive measure w/ graft failure is transfusion support -> could also use myeloid growth factors (G-CSF, GM-CSF)
  • occurs by day 28 marked by pancytopenia, marrow aplasia, and ANC < 500

Graft rejection -> could be reversed with intensification of immunosuppression

  • also marked by pancytopenia
  • important that can use molecular chimerism to define graft failure vs. graft rejection
  • difficult to manage as difficult to tell if 1) pt req more immunosuppression (to inhibit immune-mediated rejection) or 2) less immunosuppression (to enhance the “graft vs. host” reaction of donor T cells against residual host cells
  • can provide more donor immunity via donor lymphocyte infusions (DLI)
  • can provide additional stem cells if concern is graft failure rather than immune-mediated rejection


  • immunologic phenomenon; used to be defined by the temporal relationship to time of transplant
  • however, now, it is defined by the clinical features
  • interestingly, there’s an inverse relationship between probability of relapse and probability of GvHD
  • the greater the graft vs. tumor effect, the greater the potential for GvHD

Acute GvHD -> skin/liver/GI -> can occur anytime after initial engraftment but rarely beyond D+100

  • why skin/liver/GI? these are the cells that harbor a lot of antigen-presenting cells
  • 30% of pts with related-donor transplant
  • 50% of pts with unrelated-donor transplant
  • current standard of care as of 2013 was methotrexate and tacro/cyclosporine
  • skin w/ erythematous rash/desquamation, liver w/ transaminitis, GI with ileus/secretory diarrhea
  • about 50% of pts have skin findings only -> diffuse maculopapular rash w/ palms and soles involvement
  • ddx includes drug rash (but this will spare the palms and soles)
  • for liver involvement have to also include ddx of venoocclusive disease
  • will need biopsy for dx of GvHD liver
  • first line tx is 2 mg/kg methylprednisolone

Steroid-refractory GvHD -> progression after 3d of therapy or no response after 7d of therapy

  • second line tx is either biologics, TNF-alpha blockade, or chemo/phototherapy

Chronic GvHD -> resembes autoimmune disease -> 4 to 24 months post-Txp

  • generally, initial therapy is pred 1mg/kg/day AND either tacro 5-10ng/ml or cyclosporine 200-400ug/L
  • Graft failure -> the opposite of GvHD and much more rare
  • this is where the recipient’s immune system attacks the graft cells
  • typically, doesn’t happen 2/2 the immunosuppression the recipient is on
  • this is rare with HLA-matched donors -> if partially-matched graft, then you have a 5-10% risk for graft failure

Diagnostic criteria for bronchiolitis obliterans syndrome (BOS)

  • FEV1/VC < 70% or the 5th percentile of predicted
  • FEV1 < 75% predicted with > 10% decline (i.e. fast decline) over 2y
  • Absence of infection (this would disqualify it from being a “non-infectious complication of HCT”)
  • Air trapping supporting feature -> either A) air trapping on expiratory CT or small airway thickening or bronchiectasis by high-res chest CT or B) PFT air trapping (RV > 120% predicted or RV/TLC elevated over 90%

*current workup for BOS is currently an expiratory CT and PFTs; parametric mapping is currently under investigation -> therefore, should get a high resolution (i.e. helical) inspiratory and expiratory CT

Muffly Stanford 2019 – (CAR)T-Cell Therapy


  • initial remission w/ chemo but quickly followed by skin and marrow relapse <- this is unusual/aggressive
  • blinatumumab and inotuzumab w/o response
  • leukemic lesions in skin
  • (CAR)T-cell targeting CD-19 and CD-22 with refractory/relapsed B-cell lymphoma or ALL
  • relapses long-term outcomes are 10% of event-free probability (generalized badness outcome?)
  • rec’d lymphodepletion the followed by CAR T cells = day 0
  • Day+4 he developed hypoxemia req’ing HFNC c/w Grade 3 CRS
    • rec’d tocilizumab 8mg/kg x1 and dexamethasone 10mg x1
  • this pt case developed CRS 2/2 large population of the CAR T cells (see pic below) where 92% of his cells were CAR T cells:

rituximab targets CD-20

  • naked antibody targeting CD-20


  • inotuzumab approved for ALL
    • links anti-CD-22 Ab to chemotx
  • blinatumomab
    • one side CD-3 binds to T-cell; the other side binds CD-19 on surface of B-ALL

drug is the mainstay -> the problem is that remission is not durable


  • living therapy of the pt’s own immunity
  • durable
  • pt’s own T-cells usually
  • engineered to recognize tumor Ag of interest
    • different than BMT since that is taking someone else’s immunity and using for the pt
  • T-cell’s req ag presentation to get activated
  • (CAR)T-cells have receptor specific for the tumor ag of interest
    • most commonly they’re CD-19 for B-cell malignancies
    • the CAR can then recognize the tumor cell
    • then, the CAR T cell multiplies, releasing cytokines leading to tumor apoptosis
  • CAR are living therapy; the CAR can live and persist in the body, continuing to provide ongoing assassination of tumors


  1. removal of T cells via apheresis
  2. T cells are engineered to express the CAR <- 2-6 weeks sometimes for the cells to grow
  3. infusion of the T cells into the pt


  • Tisagenlecleucel is anti-CD19 chimeric antigen receptor
    • Maude N Engl J Med 2018
  • 2017 was the first lay press for ALL CAR T cell for pediatrics; then, followed FDA approval to age of 26 for diffuse large B-cell lymphoma


  • hallmark of CAR therapy
  • supraphysiologic response following immunotherapy
    • hypotension
    • fever
    • capillary leak
  • the peak of CAR T cells after infusion is approx D+7; this correlates with the peak of the inflammatory cytokines and markers (also, D+7)
  • Grade 1 = supportive care
  • Grade 2 = tocilizumab -> IL-6 antagonist FDA approved in 2017 for the treatment of CAR T associated CRS
  • Grade 3 = tocilizumab + steroids (typically, dexamethasone 10mg q6) and alert ICU
  • Grade 4 = methylprednisolone 1g x3

CRS Grading Scale.png


  • there’s some areas of the body w/o IL-6 receptors (e.g., the brain)
  • potential for the body to upregulate the IL-6 in the brain causing more severe picture


  • FDA indication currently is rheumatoid arthritis


  • FDA indication is Castleman’s disease


  • generally, encephalopathy and delirium, HA, sleep disorder
  • Stanford approach is multi-disciplinary
  • generally, the only intervention other than anti-IL drugs is steroids

Hirsch Stanford CCM 2018 – Brain Death

Coma vs. Brain death

  • coma = not awake and not aware
    • but, could still have spinal and brainstem reflexes preserved but still in coma
  • brain dead is death by neurologic criteria
  • time course for chronic phase/using “vegetative state” term
    • persistent vegetative state = 1 mo timecourse
    • 3 mo for non-trauma; 12 mo for trauma

Spectrum of cognitive and motor fxn

  • Bernat et al Annu Rev Med 2009 -> what is death/consciousness
  • spectrum -> conscious state vs. motor fxn
    • purposeful interaction with the world
    • vegetative state (APPLICABLE TO CHRONIC STATES/not ICU pts)
    • coma

Covert / functional locked in syndrome

  • adaptive tech is able to pick up their yes/no paradigms despite looking like they’re completely locked-in
  • they have awareness of the world around them
  • fMRI for example could be the adaptive tech that shows you’re able to interact w/ the world

Death (multiple different definitions)

  • legal
  • ethical
  • medical
  • biophysical -> cessation of critical fxn of the organism as a whole

Ventilator and ECMO has changed the way we view death

  • b/c can have devastating neuro injury but pt is still alive via vent; so concept of brain death didn’t come up until 1950s/when vents were invented

Brain death <- remember full brain death differs from usual death exam (central/peripheral pulse, lack of respirations)

  • functional imaging is changing the paradigm
  • binary definition; never “brain dead, except…”
  • should have a local policy at specific hospital you work at
    • variation in the types of exam and the time course between exams
  • not emergent; but, it is urgent
  • not optional to do the brain death test
    • CA law may have part where family can object? but, usually it is not optional.
  • “whole brain” vs. “brainstem” death
    • no universal definition unfortunately in society
    • whole = demonstrate that entire brain is NOT fxn’ing
    • brainstem = demonstrate that brainstem is out and not coming out -> brainstem could be out (i.e. brainstem stroke) with EEG activity on the cortex
    • in the US you have to investigate the other areas of the brain -> if they have massive pontine and cerebellar hemorrhage, you still need to do EEG to interrogate the cortex (i.e. the rest of the brain)
  • interestingly, as clearly not ALL the cells are dead
  • can say to families “irreversible brain damage” or your family has “brain damage”
    • AVOID term of BRAINDEAD unless you’re absolutely sure

Strict criteria

  • complete cessation of neuro fxn
  • cerebral circ arrest
  • testing for brain death is not optional, but in CA, the family can refuse
  • generally, a clinical diagnosis -> though ancillary testing can be performed ONLY if unable to declare clinically

Obstacles to brain death exam

  • lytes
  • e.g. of cannot perform brain death exam: cannot tolerate the apnea test (i.e. Hirsch’s first pt as attending, she put a CVICU pt on T-piece and the pt coded); cervical cord injury (you don’t know if that circuit is intact); in trauma pt missing an eye
  • severe c spine injury or max/face injury <- precluding exam
  • temp
  • severe pCO2 acidemia

Nuclear perfusion test <- this is the test of choice at Stanford

  • glucose labeled; injected at the bedside; come back 1h later and see if cerebral uptake (if uptake, then it’s not brain death); take picture of the head at bedside with nuclear imaging device (?specifically, unclear)
  • tracer takes time to obtain
  • it’s on California Ave

EEG -> has to be done in a specific way

cerebral angiogram -> looking for cessation of flow; this is gold standard at time of this lecture for “ancillary testing”

  • inject and you see vessel fill but then should see blood flow stop
  • it’s hard practically to do this b/c have to get cath lab study

TCDs <- unreliable; we don’t really use them

evoked potentials (peripheral stimulation) -> not validated for brain death; used for prognostics

Brain death exam (

  • need a cause
  • exclude confounding factors -> tox/temp, HD, uremia, hepatic failure, facial/c spine trauma, NMB
    • this one is very important; unfortunately, this part of confounding factors is under constant debate -> e.g., how many half-lives should you wait for certain drugs on board (Stanford’s policy is 5 half-lives of a medicine; things like barbituates take a long, long time)
  • do brain death exam/cranial nerves -> by two teams 1h apart; only one may need apnea test (usually, the second test is done w/ apnea exam)
    • licensed MD with experience and comfort doing the brain death exam
    • the other exam must be done by the neurology or NSGY attending

Steps to Hirch’s brain death exam (temp > 36C and SBP > 100 mmHg)

  • MAR/med review
  • normothermia (core should be > 36C); adequate BP (SBP > 100 mmHg)
  • document cause
  • document that not triggering vent -> turn down/off the backup rate and that pt not overbreathing the vent (do if you’re not worried that they’re not dangerously hypoxic)
  • document there’s no HR or BP change w/ pain
  • document no motor response w/ central/peripheral pain
  • peripheral pain; central pain
    • No response (other than spinal cord response) to painful stimuli in all 4 limbs
  • cranial nerves:
    • pupils via pupillometer
    • cold calorics in one ear; then wait 5 min until the next ear (use small angiocath) <- don’t worry about COWS mnemonic; just make sure eyes don’t move
    • corneal reflexes absent
    • oculocephalics/doll’s eyes
    • no cough/gag on deep suctioning
    • no grimace to supraorbital nerve or TMJ
  • apnea test
    • Normal PCO2 -> Then, disconnect the vent
    • Should have absent spontaneous respirations for time long enough for PCO2 to get 60 mmHg or 20 mmHg from baseline
    • *on ECMO, turn down sweep and turn down the ventilator; can run oxygen down the tube just to avoid dangerous hypoxia; usually though, ECMO pts get ancillary tests too to test brain death
    • ABG at 7 min

Donation after brain death

Donation after Circulatory Death (DCD) -> end stage disease and you’re planning to withdraw care; expectation that pt will die within 1h after withdrawal

*“thank you for bringing it up; in situations ilke this, there is a separate team that will d/w you about organ donation; they are separate from our team; when you are ready, i will step out and they can talk with you”

*ethics consult should be pursued for DCD cases <- end-stage disease where you’re thinking about care withdrawal

  • usually age < 60 for DCD cases

*”it’s very kind of you to be thinking of other people during this time, we will gather the appropriate info; in the meantime i encourage you to process the info we just provided and we’ll follow up with you soon”

ARBO 2015 – Hemorrhagic Stroke -> Aneurysmal SAH and Spontaneous ICH

Hemorrhagic stroke is divided into spontaneous ICH and SAH

  • hemorrhagic stroke has markedly worse outcomes than ischemic stroke
  • 2 types of hemorrhagic stroke -> 1) spontaneous ICH and 2) aneurysmal SAH are the two common archetypes
  • most CVAs are ischemic (80%); the remaining minority (20%) are hemorrhagic
  • median 30d mortality is 40%

Associations with a poor prognosis

  • DM
  • male gender
  • advanced age
  • posterior fossa location

Most common sites for hypertensive bleeds

  • deep perforator arteries in:
    • pons
    • midbrain
    • thalamus
    • basal ganglia
    • deep cerebellar nuclei
  • the second most common location for ICH:
    • lobar region (45% of ICH) <- this location is more common w/ cerebral amyloid angiopathy
  • less common location:
    • posterior fossa (10% of ICH) <- this is associated w/ worst prognosis



  • most likely to rupture into the subarachnoid space, but they can cause intraparenchymal hemorrhage


  • though they’re typically asymptomatic, these present more commonly w/ ICH
  • these can be anywhere in the cerebrum, brainstem or cerebellum

Brain tumor

  • rare cause of ICH accounting for ~5% of all cases
  • commonly, they’re GBMs or oligodendrogliomas or they’re mets
    • brain mets are commonly from lung cancers (as there’s high prevalence of lung cancer)

Uncommon causes of secondary ICH

  • vasculitis
  • sinus venous thrombosis
  • carotid endarterectomy
  • Moyamoya disease
  • drug use


ABC/2 formula

  • A is greatest hemorrhage diameter; B is largest perpendicular to A; and C is the product of number of CT slices and the slice thickness
  • gives ICH volume
  • “spot sign” on CT angio is the extravasation of contrast which portends hematoma expansion

ICH score for 30d mortality and 12mo functional outcome

  • GCS -> 1 point for 5-12
  • age -> 1 point for > 80 y
  • ICH vol -> 1 point for > 30 cc
  • intraventricular spread -> 1 point for yes
  • infratentorail origin -> 1 point for yes

*add the points up -> ~10%, ~20%, ~70%, and ~90% 30d mortality with point sum totals (1, 2, 3, and 4)

General ICP guidelines -> appear to have pretty much stayed the same from Morgenstern Stroke 2010 guidelines up to the more recent Hemphill Stroke 2015 guidelines

  • there’s a paucity of studies on ICP-guided therapy for ICH -> they took a lot of the guidelines from the TBI literature
  • first off, you decide if you need to insert one based upon the risk for hydrocephalus or the perceived need to drain CSF -> generally, place ICP monitor for GCS 3-8
    • maintain CPP 50-70 mmHg with an ICP < 20 mmHg
    • so, MAP goals generally 80-90 mmHg (b/c you’re assuming ICP 20-30 mmHg)

Blood pressure mgmt

  • BP is usually elevated in the ICH pts
  • In general, targeting a MAP of 110 mm Hg or BP 160/90 should be the goal
    • also, if ICP monitoring available, target CPP of 50-70 mm Hg
    • if ICP monitoring is not available, target MAP of 80-90 mm Hg b/c you’re assuming ICP is 20-30 mm Hg
  • avoid nipride and nitroglycerin 2/2 tendency to increase ICP, lowering cerebral blood flow
  • use cardene or labetalol or hydralazine or ACEi

INTERACT 2 trial

  • 2,839 pts RCT to either rapid BP lowering w/ target SBP 140 mm Hg vs. target SBP 180 mm Hg
  • there was a non-statistically significant benefit to the aggressive BP lowering <- however, this was not statistically significant

ATACH 2 trial

  • Open label RCT with intervention of targeting lower BP in ICH (targeted SBP 110-139 mm Hg) throughout the first 24hr after randomization
  • no difference in primary outcome of mRS 4 to 6 at three months out

Correction of coagulopathy

  • vit K antagonists -> lack of consensus on how to best replace vit K-dependent factors
    • 5-10 mg vit K IV, FFP, and PCC
    • PCC may have fewer complications than PCC
    • recombinant factor VII is not recommended as it will correct the INR, but not correct the other factors
  • NOACs

Anti-NMDA Receptor Encephalitis

Mechanism – autoantibodies alter the NMDAR-related synaptic transmission creating complex neuropsychiatric syndrome; there is presence of CSF autoantibodies against the GluN1 subunit of NMDAR

  • ?similar mechanism as hypofunction of NMDAR in schizophrenia
  • ?overlap of anti-NMDAR encephalitis with demyelinating disorders

Two-stage mechanism – 

First stage (3 mo or longer):

  • severe psychosis symptoms, movement disorders, coma
  • transient MRI abnormalities
  • brain biopsy/autopsy findings are B cell, plasma cell, CD4 T cells and less frequently CD8 T cells and deposits of IgG
    • of note, these findings are different from CD8 cytotoxic T cell-mediated encephalitis which has extensive neuronal loss

Second stage (duration of 6 mo or longer):

  • resolution of the first stage symptoms, but still alterations in behavior, memory, cognition, and executive functions
  • MRI changes c/w inflammation are minimal at this second stage

Prevalence – more prevalent in women with female/male ratio of 8:2

Triggers – teratoma (i.e. ovarian teratomas) and HSV are known triggers for NMDAR autoimmunity

Presentation – difficult to separate from a primary psychiatric disorder

Prognosis – 80% improved or recovered after immunotherapy or tumor removal

Definite diagnostic criteria – 

IgG GluN1 antibodies (should attempt to get CSF in addition to serum)

Exclusion of HSV encephalitis or Japanese B encephalitis (these could have relapsing immune-mediated neuro symptoms)

*and, 1 or more of the 6 sx listed in the probably diagnostic criteria (below)

Probable diagnostic criteria – 

Rapid onset (within </= 3 mo) of at least 4 or the following 6:

  1. abnormal psychiatric/cognitive behavior
  2. speech dysfunction
  3. seizures
  4. movement disorders/dyskinesias/rigidity/abnormal postures
  5. decreased consciousness
  6. autonomic dysfunction or central hypoventilation

At least 1 of the following labs:

  1. abnormal EEG
  2. CSF with pleocytosis or oligoclonal bands

Or, 3 of the above groups of symptoms and systemic teratoma

And, exclusion of HSV encephalitis or Japanese B encephalitis (these could have relapsing immune-mediated neuro symptoms)

Poor specificity of NMDAR antibodies – IgM, IgA, and less frequently IgG are present in the sera of many pts with wide ranges of disease

Seizures and risk of epilepsy with anti-NMDAR encephalitis – 70% of pts will develop seizures with variable manifestations; of note, 91% of those developing seizures survived the disease with all of them seizure-free at 31 month follow up

  • more often (47% of the time), the seizure-free status was due to immunotherapy
  • less often (16% of the time), the seizure-free status was due to AEDs
  • for the balance of the cohort, the seizure-free status was from unclear combination of immunotherapy/AEDs/spontaneous

Challenge in ICU

  • differentiating true seizure from dyskinesias and differentiating fever from  hyperthermia of primary disease or nosocomial infection
  • dysautonomic cardiac arrests (7% of a cohort studied in ICU)

Transplacental transfer of NMDAR antibodies –

Potential for neurological deficits in neonates

Systematic review of 13 pregnant patients found that 9 of the mothers recovered; 1 died. 7 of the babies were healthy but 3 had neuro deficits.

Treatment – 

First line

  • steroids
  • IVIG
  • PLEX

Second line

  • rituximab
  • cyclophosphamide (Cytoxan)

Refractory/third line

  • bortezumib (data is driven by case reports)
  • tocilizumab

No study has investigated the upfront use of rituximab


Dalmau Lancet Neurology 2019 – An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models