סיכום מילר 2024 - גרסה 1.0.pdf
Transcript
גרסה 5.6.24 – 1.0 שלום לכולם! במהלך הלמידה לבחינה ,סיכמתי לעצמי נקודות מתוך הספר.משתף פה בתקווה שזה יועיל....
גרסה 5.6.24 – 1.0 שלום לכולם! במהלך הלמידה לבחינה ,סיכמתי לעצמי נקודות מתוך הספר.משתף פה בתקווה שזה יועיל. כמה דגשים: פרקים שלא קראתי וסיכמתי בצורה מלאה מסומנים כ PARTIAL - יש בספר סתירות.מלא ,המון.בין פרקים ,בתוך הפרקים ,ואפילו בתוך אותה שורה.לכן לצערי גם בתוך הסיכום עצמו יש סתירות ובטוח גם טעויות שלי. קופסאות כתומות = הבהרות ונקודות חשובות ,טקסט ירוק = משפט או ראשי תיבות לשינון (מופיע גם כרשימה בסוף המסמך) קיצורים באנגלית שעבדתי איתם: = w/ = with, a/w = associated with, d/t = due to, hx = history, tx = treatment, pt o patient, M&M = morbidity & mortality הוספתי בסוף המסמך רשימות שהכנתי במהלך הלמידה בדגש על קונטרהאינדיקציות ,משפטי except ונוסחאות. בהצלחה !!! בכל שאלה או בעיה עם הקובץ ,אשמח לדעת. בברכת ״גם זה יעבור״, רון אשל [email protected] Chapter 9 – consciousness PARTIAL Consciousness o Awareness = ONLY subjective experience o Consciousness - Connected (external environmental stimulus) vs. disconnected (internal endogenous – dream state) o Consciousness (experiencing a stimulus) vs. Responsiveness (i.e. conscious but paralyzed) Brainstem o Locus ceruleus (LC)→ NE, a/w cortical arousal only during wakefulness o Laterodorsal/pedunculopontine tegmentum (LDT/PPT) → ACh, a/w cortical arousal during LC: דג לוקוס נורא ערני wakefulness & REM Tegmentum: מומנטום כולינרגי o Pontine reticular formation (PRF) →GABA, a/w cortical arousal PRF: תביא שקית אראף,פיייי גבי o Ventral Tegmental Area (VTA) → Dopamine, a/w arousal during exposure to anesthesia VTA :GTA releases dopamine Hypothalamus o Ventrolateral preoptic nucleus (VLPO)→ GABA and galanin. Maximally active during NREM and REM sleep, inhibits arousal centers in brainstem. ***only structure a/w sleep!! o Orexingeric neurons → maximally active in the waking state. a/w emergence from anesthesia (NOT sedation) o Tuberomammillary nucleus (TMN) → histamine, a/w wakefulness Thalamus → >50 nuclei, relays sensory input from cortex and periphery o a/w arousal, sensory processing, cortical computation, transmission arousal signals from brainstem o proposed site for “ON/OFF” switch of anesthesia → IV and VA anesthetics cause metabolic depression of thalamus, EXCEPT ketamine o Sensory nuclei in thalamus appear to be LESS involved in anesthetic-induced unconsciousness vs. higher order or “nonspecific nuceli” Long-term potentiation (LTP) → structural and functional model of memory consolidation o a/w activation of post-synaptic NMDA receptors w/ influx of Na+ and Ca+2 (calcium critical trigger for LTP) NO evidence anesthetics cause retrograde amnesia NO impairment of pictures or words presented BEFORE infusion of propofol, midazolam, thiopental, dexmedetomidine Propofol and BZDs are a/w retrograde facilitation → enhanced memory of material presented BEFORE drug administration o Some patients will not recall the immediate preanesthetic period at all – a/w ↑ age Memory: o Dexmedetomidine + thiopental → impair encoding. Propofol makes pts heavy (=consolidated) o Propofol + low dose midazolam → impair consolidation. Dex+Thio: “how do you (en)code these drugs?” Midazolam is in the middle = Dose dependent o Midazolam: low dose – only consolidation, high dose – consolidation + encoding Most anesthetics dominant effect on attention is ↓ arousal, EXCEPT Ketamine – dominant effect on orienting and selection Chapter 10 - sleep PARTIAL Sleep stages: β → α → ϴ → ϴ + sleep spindles + k complexes → mixed o “α → ϴ transition” a/w sleep onset NREM → low frequency, high amplitude. ↓ HR, ↓ temp, waxing and waning muscle tone REM → mixed frequency, low voltage. Irregularities of HR & RR. Atonia w/ occasional eye movements o ↓ skeletal muscle tone EXCEPT extraocular muscles “flip-flop switch” → mutual inhibitory relationship between arousal and sleep promoting pathways o Orexin neurons in the posterior hypothalamus project to basal forebrain and ascending arousal system (AAS) to provide excitatory, wake-promoting stimulus ▪ Ventral and median preoptic nuclei (VLPO & MnPN) → GABA-ergic neurons that inhibit orexingeric n. ▪ Narcolepsy → d/t orexin deficiency, a/w severe daytime sleepiness (“sleep attacks”) w/ cataplexy o During sleep → ↑ VLPO/MnPN inhibition of OX and AAS pathways to support sleep Respiratory events during sleep: o Apnea → ↓ flow > 90%, for at least 10 secs for at least 90% of the event o Hypopnea → ↓ flow > 30% w/ ↓ SpO2 > 4% OR ↓ flow > 40% w/ ↓ SpO2 > 3%. Event at least 10 secs o Hypoventilation → ↑ PaCO2 > 10% o Respiratory event related arousal → Δ flow not meeting other criteria and leading to patient arousal. Geniohyoid → tonic activity, but only one active at expirium Thyrohyoid → NO tonic activity, NO phasic activity Genioglossus → שריר גולסה Geniohyoid → hide! Get out Thyrohyoid → Thyrone does nothing! Obstructive sleep apnea Dx: AHI > 15 or AHI 5-15 PLUS daytime symptoms (sleepiness) OR comorbidities (HTN, Afib) o ↑ risk: obesity, elderly, male sex, smoking, allergic rhinitis, ↓ upper AW muscle tone (CNS, drugs) 1/3 of pts w/ OSA complain of S&S during wakefulness | OSA + daytime symptoms = OSA syndrome OSA is a/w cognitive dysfunction d/t brain atrophy → reversible w/ adequate tx Asymptomatic OSA may be a/w CV effects Pcrit → negative intraluminal pressure causing airways to collapse o Typically, negative (-5 cm H2O) | In OSA pts – Pcrit may be positive and collapses at sleep With onset of sleep - ↓ arousal dependent neuronal input leading to ↑ upper AW resistance o The most common pathophysiological mechanism of OSA – retropalatal obstruction of upper AW Management: o ALL patients diagnosed (moderate or mild + S&S) should be offered tx ASAP ▪ Successful tx ↓ CV risk, improves insulin sensitivity, ↑ neurobehavioral performance o CPAP (5-20 cm H2O)→ most effective tx for OSA of all severities o Oral appliances → mandibular repositioning appliance (protrusion > 50% of mandible) or tongue-retaining devices (tongue forward w/o mandibular protrusion) ▪ Recommended if mild-moderate OSA who do not tolerate, respond fail, or not candidates for CPAP tx o Tonsillectomy → adults w/ tonsillar hypertrophy | adenotonsillectomy → children w/ OSA + hypertrophy o Oxygen → NOT recommended as primary treatment Central sleep apnea → cessation of air flow w/o respiratory effort o Most common subtype → Cheyne-stokes respirations in pts w/ CHF and LV systolic dysfx ▪ Crescendo-decrescendo pattern of hyperventilation, 20-30 secs duration, 10-40 s hypopnea/apnea ▪ 50% of pts w/ CHF show CSR | M>F, worse in supine position o Tx: oxygen, respiratory stimulants (CO2, theophylline, acetazolamide), BiPAP >> CPAP Obesity hypoventilation syndrome → nocturnal and daytime hypoventilation leading to hypercapnia in obese patients (BMI > 30), w/o other causes o 50% of obese pts w/ OSA have OHS | 90% of pts w/ OHS have OSA o a/w ↑ respiratory drive | ↓ TLC, ↓ FRC, ↓ VC| o Tx: weight loss and NIV Chapter 11 – cerebral physiology Global CBF = 50 cc/100g/min, 12-15% of CO o 80% gray matter (cortex), 20% white matter o Glial cells → 50% of brain volume, but require less energy than neurons CMRO2 = 3.5 cc/100g/min → 50 cc/min (CMRO2 ≈ CBF) o 60% of brain’s energy consumption a/w electrophysiologic function o 40% a/w cellular homeostatic activity = BMR CSF o Total CSF space – 150 cc | Daily production – 450 cc (X3), peak at sleep Brain DOES NOT contain lymphatics other than glymphatic pathway o ↓ glymphatic transport w/ VAs, affected less by dexmedetomidine Anesthetic-induced EEG suppression is drug-dependent *CMR decreases to 40% of normal (=BMR) o Areas affected → Barbiturates a/w uniform depression of CBF and CMR across the brain. Isoflurane & Sevoflurane a/w relative reductions in neocortex>cerebrum, Etomidate – mainly forebrain, Ketamine – limbic > cortex o Electrophysiologic responsiveness varies between agents o EEG patterns before complete burst suppression states differ, a/w possible neuroprotective effects. Cerebral neurovascular coupling: o ↑ neuronal activity → ↑ Glutamate ➔ ▪ vascular dilation via NO (via NMDA-R), ▪ PGE2 & EET (AA metabolism via mGlu-R) Chemical regulation of CBF Regulation of CBF/CMR → autoregulated over MAP 65-150 mmHg Temperature o Hypothermia: ↓ 1 ℃ → ↓CMR 6-7% ▪ Complete suppression of CMR at 18-20 ℃ ▪ Unlike anesthetics, temp reduction beyond that DOES PRODUCE further ↓CMR ↓ temp a/w ↓ electrophysiologic function AND ↓ basal component o HYPERthermia → opposite influence! ▪ 37-42℃ a/w ↑ CBF and ↑ CMR | temp > 42 → ↓↓ CMR a/w protein denaturation PaCO2: Δ 1 mmHg PaCO2 → Δ CBF 1-2 cc/100g/min Linear, sigmoidal relationship, CBF ∝ PaCO2 | CBF varies directly w/ PaCO2 in range: 25-70 mmHg Cerebrovascular responsiveness to PaCO2 is influenced by blood pressure. ▪ Severe hypotension (↓66%) ➔ NO response to change in CO2 PaCO2 levels modulate cerebral autoregulation: ▪ hypercapnia a/w ↓ autoregulatory response | hypocapnia a/w ↑ autoregulation over wider MAP range. PaO2: PaO2 < 60 mmHg → ↑ CBF * little impact in range of 60-200 mmHg ▪ SpO2% 1⁄∝ CBF *Inversely linear, hypoxia a/w cerebral vasodilation ▪ RVLM (medulla) → oxygen sensor within brain Stimulated by hypoxia ➔ ↑ CBF, WITHOUT affecting CMR ▪ High PaO2 values a/w modest CBF decrease (1 ATM Oxygen → ↓ CBF 12%) CO: ↓ 30% CO → ↓ CBF 10% ▪ CO-CBF relationship is lost in TBI, neurologic and cardiac surgery. CBV ∝ CBF * Normal CBV = 5cc/100g of brain ▪ ↑ 50% CBF → ↑ 20% CBV (the magnitude of change of CBV is LESS than the magnitude of change in CBF) ▪ ↑ 1 mmHg PaCO2 → (↑ 1-2 cc/100g/min CBF) → ↑ CBV 0.05 cc/100g (within PaCO2 range 25-70 mmHg) ▪ ↓ MAP is a/w progressive increase in CBV as the cerebral circulation dilates to maintain CBF Systemic vasodilators → depending on MAP, but a/w ↑ CBF Nitroglycerin, nitroprusside, hydralazine, CCB The effect of vasoactive drug on CBF and CMR is dependent on basal BP, autoregulation status and BBB status Open BBB a/w ↑ effect of Norepinephrine, Epinephrine and pure β-agonists Unique: Dopamine → ↑ CBF w/o altering CMR ; Dobutamine → ↑CBF&↑CMR independent of BP effect Anesthetics and CBF/CMR IV Anesthetics ▪ All drugs ↓ CMR & ↓ CBF EXCEPT Ketamine + Remifentanil (CBF) Ketamine: ↑CMR, ↑CBF, ⟷ CBV, does NOT increase ICP in pts with TBI or nontraumatic neurologic illness. (S)-ketamine ↑↑ CMR, (R)-enantiomer ↓↓ CMR ▪ ↓ CMR: Most – Thiopental, least – MO ▪ ↓ CBF: Most – Propofol, least – MO ▪ Burst suppression can be achieved w/ barbiturates, etomidate and propofol. Inhaled anesthetics ▪ Net effect on CBF is balance between ↓CBF d/t CMR suppression and ΔCBF a/w direct cerebral vasodilation. ▪ VAs a/w direct cerebral vasodilation: increased doses (MAC >1) cause significant vasodilation w/ loss of autoregulatory CBF responses → CBF becomes pressure passive (=linear) ▪ VAs a/w ↑CBF/CMR ratio that is dose-related (NOT linearly dependent) MAC < 1 → ↓ CBF d/t ↓ CMR MAC =1 → CBF1 MAC ≈ CBFawake, no further decrease in CMR MAC > 1 → Increasing CBF d/t significant VA-mediated vasodilation HED IS flowing Vasodilator potency of VAs: Halothane >> enflurane > desflurane ≈ Isoflurane > Sevoflurane Despite differences in vasodilatory potency, autoregulation is maintained equally across all VAs ▪ @ MAC ~ 1: All VAs ↑ CBF + ↓ CMR, EXCEPT Xenon (↓CBF, ↓CMR) ▪ All VAs suppress CMR in a dose-related manner and can produce burst suppression, EXCEPT Halothane Unlike Isoflurane, Halothane a/w homogenous CBF and CMR changes throughout the brain ▪ N2O – unique! a/w ↑CBF, ↑ICP, ↑CBV, ?CMR Cerebral-vasodilating effect is attenuated in the absence/presence of other anesthetics. All drugs ↓ CMR EXCEPT ketamine (↑CMR+↑CBF) + N2O (↑CMR) All IV drugs ↓CBF EXCEPT ketamine + Remifentanil All VAs cause burst suppression EXCEPT halothane All VAs ↓ CMR EXCEPT N2O (↑CMR) All VAs ↑ CBF EXCEPT Xenon (↓CBF) Muscle relaxants ▪ Non-depolarizing → a/w indirect ↓CPP d/t histamine release (most- dTC, least – cisatracurium) ▪ Succinylcholine → can produce modest ↑ICP (~5mmHg) d/t cerebral activation) NOT C/I for RSI in neurosurgery *prevent ↑ICP w/ deep anesthesia, vecuronium, metocurine CSF dynamics Enflurane – dangerous if poor intracranial compliance, ↑secretion + ↓absorption Etomidate – a/w ↓ CSF? Enflurane – Ein Flow Halothane – Ha lo! Where did all the CSF go?? Epileptogenesis Seizures Expected Every Moment ↑ Seizure risk is a/w: Sevoflurane, Enflurane, Etomidate, Methohexital CBF and EEG EEG evidence of ischemia appear when CBF ~20 cc/100g/min ▪ 15 → isoelectric, 6-12→ reversible ischemic pneumbria, 4 weeks from CVA, 6 weeks from stable postinsult neurologic state Hypothermia: ↓ 1 ℃ → ↓CMR 6-7% Cardiac output: ↓ 30% CO → ↓ CBF 10% PaCO2: Δ 1 mmHg PaCO2 → Δ CBF 1-2 cc/100g/min o ↑ 50% CBF → ↑ 20% CBV (the magnitude of change of CBV is LESS than the magnitude of change in CBF) o ↑ 1 mmHg PaCO2 → (↑ 1-2 cc/100g/min CBF) → ↑ CBV 0.05 cc/100g (within PaCO2 range 25-70 mmHg) Chapter 12 – neuromuscular physiology and pharmacology Fade a/w: o “Open-channel block” → noncompetitive block when high NDMR concentration *post-synaptic o Decreased number of AChRs → myasthenia gravis * post-synaptic o Functional blockade → bungarotoxin * post-synaptic o Modulation of presynaptic ACh release *pre-synaptic AChR Adult ocular muscles - unique! o Tonic muscles w/ multiple NMJ on each muscle fiber that contain mature and immature fetal receptors. o Sux a/w long hard contraction d/t lack of accommodation o a/w ↑ IOP, CONTRAINDICATED if open eye injury Nerve impulse releases ACh: a/w 200 quanta of 5000 molecules each, activating 500,000 AChRs o # of quanta released influenced by concentration of Ca outside the cell (required for release) o Calcium-activated K+ Channel limit Ca entry and NT release (K+ efflux reduces Ca influx) o ↓ Neuromuscular transmission w/ ↓↓K+ and ↑↑Mg2+ → ↑↑ sensitivity to muscle relaxants “Physin” ~ “Protein” Need Ca to play tag Trafficking is a sin! Synaptic vesicle pool Brevin ~ bravo → snare drum! o Synaptic vesicle = ACh + ATP + proteins ▪ Synaptophysin – glycoprotein, Synaptotagmin – Ca sensor, Synapsin – a/w vesicle trafficking to site, Synaptobrevin – SNARE protein a/w attachment to terminal side o VP1 (reserve pool) are larger and majority, but VP2 (releasable pool) are closer to junction and the ones usually releasing NT Post-junctional AChR: *ACh binds Alpha, 2 ACh required – for each α1! o Immature/fetal→ α1 α1 β1 δ γ *long open times (X2-10), low amplitude o Mature → α1 α1 β1 δ ε *Short open times, high amplitude o Neuronal → α7 α7 α7 α7 α7 *fast and rapidly decaying α7 AChR: o Neuronal isoform – desensitized w/ choline | Muscle isoform (pathologic) – choline full agonist w/ NO desensitization ▪ Choline metabolite of ACh and Sux → activation of α7 AChR a/w continued K leakage and ↑↑K o AChR isoform most resistant to relaxants → ↓ affinity of NDMRs, many α units “available” for stimulation Neuregulin/ARIA – ErbB receptor interaction a/w NMJ maturation: o Synapse-specific, a/w schwann cell survival (pre) and γ → ε conversion (post) Mature to immature/neuronal AChR isoform a/w: o Burns o ↓ activity: fetus before innervation or after prolonged immobilization o UMN or LMN injury a/w denervation o ↓muscle protein catabolism: sepsis, systemic inflammation *NOT malnutrition Immature receptor characteristics: o Receptor t1/2: Mature - 2 weeks, Immature – SVC o Scv O2 → Central venous saturation, RA * Scv= IVC + SVC o Sv O2→ Mixed venous saturation, Pulmonary a. * Sv= IVC + SVC + Coronary v. + Thebesian v. ▪ SvO2 < ScvO2 a/w venous drainage from coronary sinus into RV Physicochemical phenomena: o Bohr: Change in O2-Hb dissociation curve d/t changes in CO2 or pH → affects O2 binding & offloading o Haldane: ↑ PaCO2 d/t ↑ PaO2 → a/w changes in CO2-carrying ability of Hb o Elevated O2 impairs HPV → ↑V/Q mismatch → ↓efficiency of CO2 exhalation Hemoglobin variants o Methemoglobin → d/t oxidation to Fe+3 a/w ↓O2 content and delivery Calculated CaO2 and PaO2 normal, ▪ a/w benzocaine, dapsone, inhaled nitric oxide (NO) * also - BUT measured O2 content is ↓↓ Prilocaine ▪ Cyanosis unresponsive to O2, tx w/ methylene blue o Carbon monoxide → X200 avidity to Hb CO2 removal is determined by alveolar ventilation (VA), NOT minute ventilation (VE) Dead space (VD) = 1/3 of each VT o ↑ dead space (d/t V >> Q) will cause compensatory ↑MV (V̇ E) to preserve alveolar ventilation (V̇ A) Functional Residual Capacity (FRC) = ERV + RV, 3-4 L o ↑FRC w/ increased height and age, ↓FRC in women and obese, ↓0.5L w/ exercise Lung compliance = ΔV/Tiraspol, normal: 0.2-0.3 L/cm H20 o VP relationship is curvilinear → ↓ compliance at extreme high or low FRC o Apical lung (↑↑PTP) is more open but less compliant. o Emphysema → extreme left shift | Fibrosis → extreme right-down shift o Chest wall Compliance = ΔV/ΔPPleural | Cllung~Clchest wall ↓ClCW a/w obesity, chest wall edema, pleural effusions, and costovertebral joint disease Airway resistance (RAW) o RAW = 1 cm/H2O/L/sec ▪ Severe asthma → ↑RAW X10 | ET tube → ↑ RAW by 5-8 cm/H2O/L/sec o Increased airflow resistance a/w ↓ lung volume or ↑ airflow rates o ~80% of resistance to gas flow occurs in the large AWs ▪ a/w turbulent flow in large tubes (Fturb=ΔP/R2 vs. Flam=ΔP/R) + branching bronchi increase cross- sectional area (terminal bronchioles CSA X10 of trachea) Lung tissue resistance → 20% of total resistance to breathing. o ↑ X3-4 in chronic lung disease | ↓ by panting respirations. Tissue inertia greatest w/ rapid ventilations Pleural pressure (PPL) gradient → less negative in base than apex o 1 downward vertical cm → ↑ PPL by 0.3 cm H20 *reduced but NOT eliminated by weightlessness Distribution of ventilation changes w/ body position o Apex a/w more negative PPL and greater distending PTP BUT is LESS aerated during inspiration d/t ↓ compliance! o d/t PPL gradient: aeration in basal (dependent) regions > apical (non-dependent) Distribution of V̇ is affected by inspiratory flow rates o Rest (low-flow) → distribution determined by compliance → base >> apex o High airflow → distribution determined by resistance → base = apex Closing Capacity (CC) = RV + CV *CC does NOT change w/ position o Increasing age a/w ↑ CC >> ↑ FRC * a/w ↓ oxygenation w/ ↑age ▪ AW closure (FRC=CC): upright >65, supine >45, supine + anesthesia >30 60 → 45 → 30 o Supine → ↓ FRC 1L → continuous closure in supine 70 y/o o COPD AW edema a/w ↑ CC → AW closure common 14th generation bronchi → Respiratory bronchioles (=gas exchange) o ↑ cross-sectional area → ↓↓ resistance → velocity = 0 at alveoli o Diffusion, NOT convection, required for transport in distal AW and alveoli Blood flow (Q̇ ): Apex >> base o Hydrostatic pressure at base vs apex is 25 cm H20 / 18 mmHg **PA pressure at apex ~ 0 West zones o Zone I: PALV > PPA > PPV; No Perfusion occurs = dead space, a/w MV o Zone II: PPA > PALV > PPV; Intermittent perfusion during systole o Zone III: PPA > PPV > PALV; Perfusion throughout entire cardiac and respiratory cycle, flow NOT affected by gravity o Zone IV: PPA > PPV > PALV; ↓↓perfusion d/t compression of extra-alveolar vessels Pulmonary capillary Δ PO2 driving pressure: (PaO2 – PmvO2) = 100 – 40 = 60 mmHg Changes w/ Anesthesia: o ↑RAW o ↓ FRC 2-3.5 L (~20%) ▪ NOT a/w controlled vs. spontaneous breathing, IA vs. IV anesthesia or muscle paralysis o ↓ Compliance ▪ Total respiratory system Cstatic 95→60 mL/cm H20, Mean Cstatic 190→150 mL/cm H20 Atelectasis → 90% of anesthetized pts!! *15-20% of lung even before surgery starts o NOT a/w controlled vs. spontaneous breathing, IV vs. IA, COPD status, or ↑age o ↑ atelectasis a/w ↑BMI and ↑FiO2 | atelectasis in base > apex o Thoracic surgery & CPB a/w larger but shorter atelectasis than after abdominal surgery o % of atelectasis ∝ size of pulmonary shunt → hypoxemia o Atelectasis + AW closure a/w 75% of overall oxygenation impairment Prevention of atelectasis o PEEP ~7 cm H2O (if BMI40 ▪ Reversal of hypoxemia is NOT proportional w/ applied PEEP – threshold effect ▪ PEEP a/w ↑ shunt d/t ↑ flow to closed dependent lung regions (base) + ↓ flow non-dependent regions o Recruitment maneuvers → Paw of 40 cm H2O for 7-8 secs o ↑ FiO2 a/w atelectasis (pre and post op) d/t gas resorption ▪ ↓ resorption during induction w/ ↓FiO2 (2 Apex: V > Q, base: Q > V o When moving down the lung: ↑Q (X10) >>>> ↑V (X3) Effect of anesthesia to ↑shunt% + ↑ V/Q mismatch (↑log SDQ), increases w/ age o Minimal derangement added by muscle paralysis or spont. ventilation Major cause of impaired gas exchange o Preexisting lung disease a/w impaired gas exchange BUT w/ ↓atelectasis and ↓shunt!! o Age 50: V/Q mismatch *anesthesia worsens v/q mismatch as 20 yrs of aging Atelectasis Shunt (Q̇ s) V/Q mismatch does NOT ↑ w/ age ↑ w/ age ↑ w/ age * Infants > adults * EXCEPT age 23-69 ↑ age a/w ↑FRC, ↑Shunt (69), ↑V/Q mismatch, BUT NOT atelectasis! Hypoxemia 1. Hypoventilation = PaCO2 > 45 mmHg A-a gradient → 3-5 mmHg, ↑gradient implies the presence of an additional cause to hypoxemia other than only hypoventilation (i.e. V/Q mismatch, diffusion defect….) 2. V/Q Mismatch → most common cause! In healthy lung range of V/Q ratio (0.5 at bottom, 5 in the apex) 3. Impaired diffusion Most noticeable during exercise - O2 transit time too fast to equilibrate. 4. R→L Shunt V=0 in a region, d/t collapse (atelectasis) or consolidation (pneumonia) Shunt always ↓ PaO2 at any FiO2! ** response to O2 negligible when shunt% > 30% Hypoventilation - only COPD Asthma – only V/Q mismatch Atelectasis – only shunt Diffusion impairment: emphysema, fibrosis and pulmonary edema V/Q mismatch in all disorders EXCEPT atelectasis Shunt in all disorders EXCEPT obstructive diseases (COPD+asthma) Biggest shunt – ARDS Biggest v/q mismatch - Emphysema CO2 pneumoperitoneum causes improved oxygenation a/w ↑atelectasis + ↓shunt o Paradox! Explanation: hypercapnic acidosis potentiating HPV Epidural anesthesia a/w NO CHANGE in FRC/CC relationship or V/Q ratios One-lung ventilation o Inhaled NO (pulmonary vasodilator) + IV Almitrine (pulmonary vasoconstrictor) ➔ improved oxygenation o a/w Almitrine potentiating HPV and ↓ perfusion to nonventilated areas (↓shunt) Cardiac surgery – Postop o Gradual resolution of atelectasis a/w residual shunt ~30% by day 1-2 o Recruitment up to 46 cmH2O DOES NOT affect PVR or RV afterload REM Sleep a/w ↓10% in VE & ↓ 10% in FRC Chapter 14 – cardiac physiology P WAVE - onset of atrial systole with depolarization of the SA node - ventricular volume increases with atrial kick - ascending a wave R WAVE - peak a/w isovol. contraction, closure of mitral valve + 1st heart sound - beginning of c ascent that peaks when the 1st sound ends ST SEGMENT - increase in aortic blood flow, decrease in ventricular volume - x descent starts and finishes when T begins T WAVE - end of T wave coincides with isovol. relaxation, 2nd heart sound, middle of v ascent. * End of isovolumetric relaxation a/w opening of mitral valve --> 3rd heart sound, peak of v followed by y descent, no ECG activity. MITRAL VALVE opens: v wave peak, no ECG activity. closes: beginning 1st sound, end of a-beginning of c, peak of R AORTIC VALVE opens: end of 1st sound, peak of c, after S wave. closes: 2nd sound, rising v wave, end of T. Systole – 3 stages: Isovolumetric contraction → Rapid ejection → Reduced ejection. Diastole – 4 stages: o Isovolumetric relaxation → energy-dependent, does NOT contribute to ventricular filling o Rapid ventricular filling, 80% o Reducing ventricular filling – diastalsis, 5% o Atrial systole → 15%/25% of total ventricular filling RV → crescent-shaped, inflow & outflow NOT simultaneous, much of contractile force from LV-based septum Afterload is assessed by aortic impedance (𝑑𝑃⁄𝑑𝐹𝑙𝑜𝑤) *SBP may estimate afterload if NO AS Myocardial O2 demand depends on wall stress and heart rate o Wall stress (σ=P·R/2h) is maintained by compensatory hypertrophy (↑h) to offset ↑P Frank-Starling curve → a/w Δ sarcomere cross-bridging. o Key component → length-dependent shift in sarcomere Ca+2 sensitivity Cardiac Work → a/w O2 consumption o External work → “stroke work”, calculated as SV · P Internal work → a/w heart inefficiency, directly proportional to wall stress. o Cardiac output (CO) o Determined by HR, contractility, preload, and afterload Fick principle: q1 (pulmonary artery) + q2 (alveoli) = q3 (pulmonary veins) Cardiomyocytes o ventricular (140μm) >> atrial (20 μm) | 50% myofibrils (80% contractile proteins), 50% cellular organs Intercellular junctions: spot desmosomes –> anchor intermediate filament cytoskeleton, sheet desmosomes (fasciae adherens–> contractile apparatus Fast-response AP → His-purkinje system o Phase 1 – transient repolarization → transient efflux K+ current Ito o Phase 2 - plateau phase → Ca+2 influx (L-type channels) w/ K+ efflux (Ik, Ik1, Ito) o Phase 3 – repolarization → K+ efflux >> Ca+2 influx Slow response AP → pacemaker cells, spont diastolic depolarization during phase 4 o a/w ↑ 3 inward (ICaL, ICaT, If)+ ↓ 2 outward currents (Ik,Ik1) ▪ If → mixed cation flow, principal determinant of depolarization duration o Phase 0 – less steep, phase 1- absent, phase 2 & 3 indistinct. SERCA pump: ATP dependent pump returning Ca back into SR → promotes relaxation o 90% of all SR proteins | Ⓟ-phospholamban a/w ↓inhibition and ↑ SERCA activity o β-stimulation causes phosphorylation → ↓phospholamban activity → ↑ SERCA activity ➔ lusitropic effect Zumba Instructors Always Have Muscles Sarcomere = distance between Z-lines o A-band → unchanged during contraction, contains actin & myosin o 3 filaments proteins: Actin (acTHIN), Myosin, Tintin (myosin-Z line tether) o Troponin complex: TnC (Ca receptor), TnI (inhibitor), TnT (links to tropomyosin) o Rate of cross-bridge cycling is dependent on activity of myosin ATPase Familial hypertrophic CM → AD (8), sarcomeric disease VS. Familial dilated CM → AD (4) + X-linked (2), cytoskeleton disease Neural cardiac regulation → through g protein-coupled receptors (GPCRs) o Parasympathetic → ACh, supraventricular tissues, dominant tone at rest *M2-R most common o Sympathetic → NE, ventricular tissues, more prominent in exercise or stress ▪ α 1A & α1A → ↑ inotropy d/t ↑iCa+2 * α 1A mediates cardiac hypertrophy ▪ β → ↑chronotropy, ↑inotropy , ↑lusitropy, d/t ↑Ca+2 β1-ARs → atria + ventricle | β2-ARs → atria >> ventricle β1 density >> β2 BUT cardiostimulant effect β2>β1 d/t tighter coupling to cAMP pathway ***α1→ PLCβ only, NO cAMP effect | α2→Gi only, ↓cAMP | β→mixed, ↑/↓ cAMP Cardiomyocytes produce angiotensin II that stimulates AT receptors. o AT1R → predominant subtype, a/w positive chronotropic and inotropic effect, BUT involved in cardiac hypertrophy w/ adverse myocardial remodeling *blocked by ACEi o AT2R → antiproliferative, upregulated w/ ischemia or injury Cardiac sex hormone receptors → nuclear (modulate gene expression) & nonnuclear (i.e. ↑NO synthase activity → vasodilation) o CHF a/w ↓thyroid and growth hormones, but NO EFFECT on sex hormones & VIP Baroreceptor reflex (carotid sinus reflex): changes in BP cause changes in autonomic tone o Responsible for maintenance of BP within preset value via negative- feedback loop ▪ Chronic hypertension → new preset value, often ↓ reflex response o Strech receptors in carotid sinus and aortic arch, via CN 9 + CN 10, to nucleus solitarius (medulla) ▪ SBP > 170 ➔ ↓ sympathetic activity + ↑ parasympathetic ▪ Hypotension ➔ reversed! o ↓ efficiency when BP < 50, volatile anesthetics (particularly halothane), CCB, ACEi, PDEi Chemoreceptor reflex: ↓PaO2 (45 mmHg, a/w dysphagia and chest pain. Gastric motility and emptying: o ↑ emptying: gastric distention, gastrin, motilin, NO o ↓ emptying: duodenal distention, high fat content (a/w ↑cholecystokinin), opioids, vasoactive drugs, hyperglycemia, ↑ICP, mechanical ventilation **Gastric emptying test → time to emptying of 50% of meal w/ tracer Small bowel manometry → evaluates SI motility by evaluating contractions at fasting, eating, postprandial o Myopathic cause (MMC absent or phase III < 40 mmHG) VS. neuropathic (uncoordinated contractions or postprandial antral hypomotility) Migratory motor complex (MMC) → small intestine, every 45-180 min *only during fasting! o 3rd phase (of 4) → peak electrical and mechanical activity w/ regular high-amplitude contractions Giant migrating complexes (GMC) → large intestine. o 6-10 events/day | mean amplitude 115 mmHg | distance 1 cm/s for 20 seconds o Diarrheal IBS a/w ↑GMC, Constipated IBS a/w ↑/absent GMC | IBD a/w ↑ GMC frequency Anesthetic agents & GI *NO DIFFERENCE in outcomes between different agents!! IV and VA! o General anesthesia causes a loss of ALL protective reflex o Midazolam → ↑ duration of MMC phase III w/ ↓overall MMC length (by 27%) BUT no overall difference o VA a/w ↓contractile and propulsive activity, dose-dependent ↓ splanchnic oxygenation ▪ Recovery: small intestine → stomach (24 hrs) → colon (30-40 hrs) ▪ Desflurane → a/w sympathetic activation surge, but no lasting effect o IV agents ↑ intestinal motility, but NO affect on recovery or inflammatory response o N2O gut distention correlated w/ amount of gas in GI, duration & concentration of administration. o NDMR → effect skeletal muscle, GI motility remains intact o Succinylcholine → ↑ intragastric pressure a/w reflux risk (intragastric pressure >> LES pressure) Opioids & GI o ↓ GI motility and constipation NOT a/w opioid tolerance o Peripheral μ-activation ▪ Myenteric plexus → delayed gastric emptying w/ slow transit time, ↑resting tone Dual effect: inhibits excitatory pathways and inhibits inhibitory pathways ▪ Submucosal plexus → constipation d/t ↓nutrient secretion + ↑ fluid absorption Mesenteric Ischemia – 4 stages: o Hyperactive peristalsis → paralysis → ↑permeability of fluids & electrolytes → Shock (if necrosis) Resections o SI maintains function if at least 1/3 remains o Jejunal resection → function replaced by ileum o >100cm of Ileum resected → severe B12 and bile salts malabsorption, a/w diarrhea. Postoperative ileus → mostly d/t manipulation of the intestines, resolves within 3-4 days o Early neurogenic phase → 3-4 hrs, ↑ sympathetic activity decreases GI motility o Late inflammatory phase → starts w/ manipulation. widespread inflammation a/w ↑permeability ▪ Main pathophysiologic event is neuroimmune interaction (immune system-ANS) o ↑ transit time: stomach 24-48 hrs, colon 48-72 hrs o Epidural block a/w ↓postop ileus by 36 hours ▪ Improved GI and anastomotic mucosal blood flow a/w ↓sympathetic activity o Early postop ambulation a/w prevention and treatment *NO correlation w/ extent of ambulation Viscera innervation o Myelinated A-δ fibers + unmyelinated C fibers o “Dual function” → efferent that carry sensory fibers and afferents that regulate autonomic flow o Visceral innervation distribution is diffuse and capable of amplification, “vicious cycle” of self aggravation Sympathetic Parasympathetic Upper GI organs T5-L2 Vagus n. to myenteric & submucosal (upper abdomen, stomach, pancreas, Sympathetic trunk to celiac plexus plexus SI, proximal colon) Lower GI organs T9-L3 Pelvic (S2-S4) nerves (descending colon, sigmoid, rectum, Inf. mesenteric & hypogastric plexus bladder, lower ureter) Function A: Visceral pain A: Satiety, nausea, distention E: ↓motility, GI vasoconstriction E: ↑peristalsis, sphincter relaxation Sympathetic Celiac plexus EXCEPT sigmoid + rectum (inf. hypogastric) Parasympathetic Vagus nerve EXCEPT descending colon & sigmoid + rectum (pelvic nerves) Celiac plexus → 0.5-4.5 cm, located close to celiac trunk within the prevertebral retroperitoneal space o Greater splanchnic n. (T5-T9) + Lesser splanchnic n. (T9-T11, present in 70% of cases) Visceral pain blocks → a/w blockade of sympathetic nerves only! Parasympathetic remain intact. o Spinal anesthesia to at least T5 ▪ 20% nausea & vomiting d/t unopposed vagal activity w/ GI hyperperistalsis o Epidural anesthesia covering T5-T12 o Sympathetic trunk block: Paravertebral or selective blocks T5-L2 o Celiac/splanchnic nerve block ▪ NO objective signs to verify – hypotension NOT regular finding ▪ Most devastating → vascular trauma, thrombosis, retroperitoneal hematoma Epidural o Lumber → preservation of stressed volume and blood pressure o Thoracic → mesenteric hypotension w/ intestinal blood flow maintained. ▪ TEA + fluid infusion → ↑stressed + ↑unstressed, ↑ TBV ▪ TEA + adrenergic agonist → ↓unstressed to ↑stressed, ⟷ TBV ERAS o Preoperative oral carbohydrates ↓ insulin resistance 50% o Avoid hypothermia → a/w ↑SSI X3 o Fluid optimization (restricted > liberal) Chapter 16 – Hepatic physiology and pathophysiology Liver → 600-1800g, 2-2.5% of totally body weight *contribution to TWB ↓ w/ age o Functional midline → Cantlie’s line, at bifurcation of Portal v. o 4 sectors split by hepatic veins, 8 segments split vertically by portal v. branches ▪ 4 Sectors: Rt. Post (6+7), Rt. Ant (5+8), Lt. Medial (1+4), Lt. Lateral (2+3) Blood supply --> 25% of CO o 30% Hepatic a. (80% celiac trunk, 20% SMA), 70% portal v. *50:50 O2 delivery! Anatomic unit – Lobule: hexagonal, 6 triads + 1 central vein Functional unit – Acinus: triangular, 2 triads + 2 veins Sinusoids → nutrient rich blood from triad to hepatic veins o Sinusoidal endothelial cells → separated by fenestrations 50-150 nm to Space of Disse o Hepatic stellate cells → 8-10% liver cells, hepatic “stem cells”, a/w differentiating into myofibroblasts participating in hepatic inflammation and fibrosis. Hepatocytes → 75-80% of total cellular hepatic volume o Basolateral (sinusoidal) – SD, apical – forms bile canaliculus o Periportal Zone 1 → aerobic metabolism, glycogen synthesis, sulfation o Perivenous Zone 3 → anaerobic metabolism, glycolysis, bile acid synthesis, glucuronidation + CYPs (Phase III+I metabolism) *most sensitive to hypoxia! ▪ Bile acid + Glutamine → only “synthesis” on dominant on PV side of acnius Myeloid Cells o Kupffer cells → 20-30% of nonparenchymal cells, 80-90% of all tissue macrophages. Reside in sinusoids, a/w innate & adaptive immunity. o Dendritic cells → promote tolerance to phagocytosed particles o Myeloid-derived suppressor cells → suppress immune response in lover, a/w viral persistence in chronic viral hepatitis Lymphocytes → throughout liver parenchyma, a/w innate & adaptive immune responses. Hepatic drug metabolism o Phase I → CYP450 + non-CYP450, convert lipophilic to hydrophilic molecules o Phase II → conjugation (most common – glucuronidation), to make more products more water soluble ▪ Polar molecules undergo Phase II WITHOUT phase I o Phase III → active excretion into sinusoids or bile by transmembrane transporters (ABC transporters) First-pass metabolism → gut or liver o a/w ↓oral bioavailability Liver synthesizes 80-90% of circulating proteins, mainly Albumin (>50% of total plasma protein) Fatty acid oxidation regulated by supply of FA, amount of microsomal esterification & acetyl-CoA present Bile → 400-600 cc/day, 95% reabsorbed *95% water Coagulation o Produces all factors EXCEPT 3,4,8 (vWF), Thrombomodulin, tPa and urokinase o Vitamin K-dependent gamma-carboxylation: 2 7 9 10 C S *Inhibited by Warfarin Heme synthesis → 10-20% in liver, 80-90% bone marrow o a/w available free heme pool in the body, NOT free iron! o Acute intermittent porphyria → 5-10:100,000; Porphobilinogen deaminase deficiency. ▪ Triggers: erythromycin, trimethoprim, rifampicin, phenytoin, barbiturates ▪ Poorly localized abdominal pain (>90%), hyponatremia (40%), dark red urine Aminotransferases → DO NOT represent extent of liver damage. o *GNG enzymes → a/w acinar zone 1 | Normal ranges differ w/ gender & BMI o AST/ALT ratio: Hepatic injury < 1; Wilson & Alcoholic liver disease >1 LDH → nonspecific marker of hepatocellular injury *↑LDH + ↑AP a/w malignant infiltration of liver GST o Short t1/2 of 60-90 minutes → marker of early injury; present in cells throughout all acinar zones AP → canalicular membrane of hepatocyte o Varies w/ gender, age, blood type, and smoking | t1/2 = 1 w → normal in early biliary obstruction o ALT:AP > 5 a/w hepatocellular injury, ALT:AP < 2 a/w cholestatic disease Bilirubin o Bilirubin in urine a/w ↑conjugated form | Massive hemolysis a/w ↑conj+↑unconj, but more unconj Albumin o t1/2 = 20 days, does not reflect acute Δ in synthetic function | Pre-albumin → better reflects protein nutrition o ↑Bilirubin a/w ↓prognosis in acute or chronic liver disease ↑ PT/INR → not specific for liver disease! o Coagulation factors have short t1/2 → reflect acute liver failure early! * F7 – 4 hrs, Fibrinogen (F1) – 4 days AFP > 1000 ng/mL common in pts w/ HCC o Levels used to monitor HCC disease progression, but NOT specific enough for HCC screening PIVKA-II → shorter t1/2, used to monitor treatment response and recurrence Unlike clearance methods (ICG, MEGX..), Indicator dilution techniques measure hepatic BF even in liver dysfx HCC cells receive their blood supply primarily from the hepatic a. (unlike normal parenchyma – Pv.>Ha.) o HCC on CT w/ contrast: hyperintensity in arterial phase, washout during portal venous phase. Prognosis/markers MEGX clearance predicts poor outcomes in chronic HCV pts Cholestatic disease → ↑ AP, ↑ GGT + ↑ Bili o ↑AP a/w early sign in asymptomatic patients Primary Biliary Cholangitis → Intrahepatic ducts PBC → F>>M, age > 60, inside & quiet, mitochondria – from mother o 90% Female, 6 decade | 60% asymptomatic at dx | Presenting symptom → fatigue & pruritis th o Dx: ↑AP for >24 weeks + AMA titer > 1:40 | Biopsy → interlobular bile duct lesions o a/w Cirrhosis and liver failure WITHOUT ↑HCC risk | ↑ Bilirubin + ↑ AP a/w poor outcome o UCDA tx → 60-70% response w/ ↓ AP+ ↓ Bili, response ∝ prognosis Primary Sclerosing Cholangitis → Intra- & extrahepatic ducts o M > F, 3-4th decade | 50% asymptomatic at diagnosis | Presenting symptom → fatigue & pruritis o Most patients have IBD (UC > CD) | a/w Hypergammaglobulinemia | Liver transplant – only effective tx! Cirrhosis → endpoint disease o Etiology: West – alcoholic liver disease, HCV, NASH | East – Hepatitis B o Earliest marker → Thrombocytopenia * a/w ↓thrombopoietin & splenic sequestration o Risk stratification based on poHTN, varices, and synthetic dysfunction. ▪ Decompensated cirrhosis = ascites, variceal hemorrhage and/or hepatic encephalopathy Portal Hypertension = HVPG > 5 mmHg o HVPG – gold standard but invasive | Liver stiffness > 20 kPa a/w significant poHTN (LI 20 ~ HVPG >10) o Dx by US: portosystemic collaterals or portal venous flow reversal * sufficient for dx o Tx to ↓HVPG: non-specific βB (propranolol, timolol), carvedilol, variceal ligation o Acute variceal hemorrhage → Ceftriaxone, vasopressor infusion (Somatostatin, Octreotide, Terlipressin) Ascites → a/w 1-year mortality of 20% o Tx: sodium restriction, nonspecific βB, diuretic (Spironolactone, furosemide), Midodrine Renal failure → 40% of hospitalized ESLD patients, a/w poor prognosis o 70-80% precipitated by hypovolemia or bacterial infection. Hepato-Renal Syndrome o Dx of exclusion! AKI w/o an apparent cause + unresponsive to volume expansion o Type 1 → rapidly progressive, X2 creatine within 2 weeks, poor prognosis o Tx: NE infusion, albumin boluses, Terlipressin, Octreotide + Midodrine | Liver transplant – definitive tx. Hepatic Encephalopathy o a/w decompensated cirrhosis o 30-40% of pts w/ cirrhosis, 50% w/ shunts o Grading: I – disordered sleep; II – asterixis, ΔLOC; III – confusion, ↓LOC ; IV – Coma. o Tx: lactulose, rifaximin – ↓ recurrence. Hepatopulmonary syndrome = A – a > 15 mmHg (room air, sitting) o 25% platypnea (dyspnea supine to standing) or orthodeoxia (↓PaO2 >5%/4mmHg supine to standing) o Severity ∝ PaO2: mild >80, moderate 60-80, severe 50-60, very severe 88% | Liver transplant only effective tx! Portopulmonary hypertension o Dx w/ right heart catheterization: mPAP > 25 mmHg, PVR > 240 dynes/s/cm5, PAWP < 15 mmHg o Severity ∝ mPAP: mild 25-35, moderate 35-45, severe >45 | Screen If RV SP > 50 mmHg o Tx to ↓PVR : PDE5i, prostacyclin analogs, endothelin receptor antagonists o Severe PoPH (mPAP >45) → absolute CONTRAINDICATION to liver transplantation! Hepatic hydrothorax o 5-10% cirrhotic pts | Rt > Lt | Tx w/ sodium restriction and diuretics | TIPS - if refractory Hepatocellular carcinoma o M > F | Most important RF – chronic liver disease |No definitive staging system | Tx: surgical resection Liver transplant only effective treatment: Primary sclerosing cholangitis Hepato-pulmonary syndrome ** Note: definitive tx for HRS THBF = PBF + HABF * maintained via the hepatic arterial buffer response o VAs a/w preservation of buffer response, EXCEPT halothane IV agents: ↑ effect / ↓ elimination Unchanged Midazolam Fentanyl Drug elimination reduced w/ Dexmedetomidine Sufentanil advanced liver disease: Morphine Remifentanil Vecuronium, Rocuronium, Meperidine Cisatracurium Morphine, Meperidine, BZDs Alfentanil Sugammadex Rocuronium Neostigmine Anesthetics excreted in bile: Vecuronium Diazepam, Lorazepam, Succinylcholine Morphine, Phenytoin Mivacurium Non-hepatic surgery o Acute hepatitis or liver failure → elective surgery is CONTRAINDICATED! o Compensated chronic liver disease → NO increased risk o Cirrhosis → ↑ X3-8 morbidity and mortality *Greatest risk – CABG Risk factors for ↑ postop M&M: o Male, ↑ age, renal failure, ↑ASA, emergency surgery Child-Turcotte-Pugh Score (CTP): o Albumin, Bilirubin, PT/INR, Ascites, Encephalopathy Child learns ABCDE *D=Dump=Ascites o 30-day postop mortality: A (5-6) → 2-10%, B (7-9) → 12-31%, C (10-15) → 12-82% ▪ Lower risk in laparoscopic surgeries (A 2%, B 12%, C 12%) MELD score o Bilirubin, PT/INR, creatinine, etiology *NOT albumin o Survival: 100 → 99% → 90% → 60% → 10% → 0% ▪ 30-day postop mortality: 20 → 50% o MELD score ∝ wait-list mortality | HCC-MELD score (MELD + AFP + tumor size) → predicts survival after liver transplant in HCC pts. TIPS → portohepatic shunt to ↓poHTN * Goal: HVPG < 12 o Contraindications: CHF, TR, mod-severe pulmonary HTN o Preop blood transfusion if HB 2, PLT < 50,000 | 1-2% major complication – hemorrhage Hepatic resection: o Laparoscopic if 40% w/ cirrhosis. ↑Transfusion risk: o Anemia, extrahepatic surgery, caval exposure, >3 segments, ↓PLT, cirrhosis, repeat surgery, tumor size Pringle → hepatoduodenal ligament (contains hepatic a. + portal v.) o a/w hepatic ischemia and reperfusion injury | 15-20 min on – 5-10 off, total ischemia time < 120 min o Sevoflurane → a/w hepatic pre & post ischemic conditioning Hemi-hepatic inflow occlusion → selective Pv. & Ha. Clamping NO benefit vs. Pringle! Total hepatic vascular occlusion → Hepatic a., Portal v., Supra-&Infrahepatic IVC Postoperative coagulopathy and thrombocytopenia → 21-100% of pts! o INR peaks POD 1-2, PLT nadir POD 3-4, return to baseline by POD 4-5 o RF: cirrhosis, preop INR > 1.3, preop PLT < 150K, EBL > 1000cc, ↑duration of surgery Chapter 17 – renal physiology Kidney → 2.5% of TBW but a/w 20% of CO and 7% of total O2 consumption o BF to cortex (94%) >> medulla (6%) → Medulla sensitive to hypoxia o Metabolically active mTAL → most susceptible to ischemia o Renal AV oxygen difference 1.5 mL/dL 1 million nephrons o 70-80 % short cortical, 20-30% long juxtamedullary Filtration barrier → size-selective (GBM) and charge-selective (negatively charged glycocalyx) Efferent a. vasoconstriction a/w ↓ RBF but GFR preserved for longer Afferent a. vasoconstriction a/w ↓ RBF w/ decreasing GFR Sympathetic activation → mainly α-induced vasoconstriction o Mild: Efferent a. constriction, small effect on Afferent a. → ↓RBF w/ ⟷ GFR o Severe: Efferent & Afferent a. constriction → ↓RBF w/ ↓ GFR Angiotensin II → Efferent a. vasoconstrictor + maintains filtration fraction o AT1R on luminal and basolateral surface → ↑ tubular H2O & Na reabsorption o AT7R → vasodilation via ↑NO and prostaglandin-mediated natriuresis AVP/ADH → Efferent a. vasoconstrictor + ↑ water reabsorption o AVP secretion threshold 280-290 mOsm/kg. ↓ RBF o Strongest trigger: systemic hypotension, NOT osmolarity! ↓ GFR ↓ UO o 3 sites of action: DCT, collecting tubule, collecting ducts o V1A → cortical efferent a. vasoconstriction | V2 → ↑ medullary aquaporins to facilitate water reabsorption o AVP secretion NOT affected by anesthetics | surgical stimulation a/w ↑ AVP secretion, lasts 2-3 days postop Aldosterone → ↑ tubular reabsorption of H2O & Na via Na/K/ATPase pump on basolateral side o Triggers: ↑ K+, ↓ Na+, ATII, ACTH o Unlike the immediate effect of ATII, aldosterone delay 1-2 hrs to action o Binds receptor on principal cells (DCT) → Aldo-receptor travels to cell nucleus → channel synthesis → Apical Na channels, basolateral Na/K/ATPase pump Prostaglandins (eicosanoids)→ a/w renal protection d/t maintenance of cortical BF o ↑PG synthesis (by Phospholipase A) a/w ischemia, hypotension, NE, ATII, AVP o Protects kidney from its own stress mediators → promotes vasodilation of juxtaglomerular vessels via ↑cAMP Kinins → direct vasodilators Natriuretic peptides → vasodilation via ↑cGMP ↑ RBF ↑ GFR o Afferent a. dilation + Efferent a. → ↑GFR & ↑ GFF, regardless of RBF! ↑ UO o Inhibit aldosterone secretion and subsequent effects | Inhibit AVP release Dopamine → a/w vasodilation and natriuresis o DA1R → ↑cAMP a/w renal vasodilation | D2R → ↓NE release from presynaptic sympathetic fibers Adenosine → renal protection a/w RBF regulation | Ischemia a/w ↑adenosine X5 Nitric Oxide → potent vasodilator o Inhibits apical Na/H cotransport | Inhibits sodium reabsorption in mTAL | counteracts ROS vasoconstriction Receptors - AT2 → apical & basal membrane receptor - AVP → basolateral GCPR, a/w ↑ cAMP - Natriuretic peptides → basolateral receptor, a/w ↑ cGMP - Aldosterone → hormone, cytoplasmic receptor Glomerular filtration (GFR) o 180 L/day filtered → 1.5 L/day urine excreted o Reabsorption: Glucose 100%, Urea 50%, Cr 0% Proximal Convoluted Tubule o Apical border – tall microvilli, basal – multiple mitochondria o Only 10-15% of RBF, but 80% of renal energy required for Na/K-ATPase to maintain osmotic gradient o PCT a/w reabsorption of 65% of refiltered Na, Cl, and water ** NOT K! Loop of Henle o Maintains osmotic gradient in the interstitial by the countercurrent system o Descending loop – water permeable, medullary & cortical thick limbs – impermeable to water o mTAL → Na+/K+/2Cl- cotransporter, inhibited by Fusid | Paracellular reabsorption of Na, K, Ca, Mg. Collecting tubules o Principal cells → resorb Na & K | Type A IC → active H+ secretion | Type B IC → secrete HCO3- & reabsorb H+ o AVP required to facilitate tubular H2O reabsorption to maintain interstitial osmotic gradient o With high AVP levels, Osmurine = Osmmedulla Myogenic RBF autoregulation → Afferent a. vasoconstriction o Compensates for changes in pressure within 3-10 secs over BP range of 70-130 mmHg Glomerulotubular balance → compensates for ↑GFR a/w ↑BP by ↓tubular absorption o ↑ NaCl distal delivery stimulates the renin-angiotensin paracrine cascade → ↓ GFR through ATII constriction of the Afferent a. Tubuloglomerular feedback o Range: NaCl concentration 15-60 mmol/L, w/ maximal response at >60 mmol/L. o Net tubular filtration pressure = 32 + 6 – (15 + 3) = ~8 mmHg (favors resorption) Osmolality → omsoles of solute per Kg of solvent (Osm/Kg) Osmolarity → number of osmoles of solute per liter of solution (Osm/L) o Osmolarity (Osm/L) = 2·Na + 2·K + BUN(mg/dL)/2.8 + Glucose(mg/dL)/18 o Affected by changes in water content, temperature, pressure o Osmolarity > osmolality Urine osmolality can range from 40 to 1400 mOsm/L Medullary interstitium → hyperosmolality near 1200 mOsm/L o Maintained by the countercurrent multiplier effect of the LoH o Creates a standing osmotic gradient in the vasa recta following the LoH: ▪ Cortex 300, juxtamedullary zone 600, deep medulla 1200 mOsm/L Urea → contributes 40-50% of the medullary osmolality, 50% reabsorbed o Urea transporters activated by AVP transfer urea into interstitial fluid in medulla o Recirculates via thin limb of LoH to maintain medullary osmotic pressure Hypovolemia → ↑ sympathetic outflow, RAS activation, AVP release o Sodium reabsorption increases (66→80%) → highly concentrated urine (Uosm 600) w/ low sodium (UNa 10) Hypervolemia → ↓ sympathetic outflow, ANP release o Sodium reabsorption decreases (66→50%) → dilute urine (Uosm 300) w/ abundant sodium (UNa 80) Urine output → NOT a/w renal failure o Perioperative oliguria ( 10 min OR (2) < 60 mmHg for 11-20 min Fenoldopam (Selective D1 agonist)→ causes hypotension w/o ↓RBF Kinetics → getting drug to site of action Dynamics → changes made, = pharmacologic effect Chapter 18 - pharmacology Pharmacokinetics → body does to drug, Pharmacodynamics → drug to body Time course of IV drugs depends on Vd and clearance Volume of distribution = amount/concentration, represents the degree to which a drug is distributed in body tissue rather than the plasma o peripheral distribution increases Vd o In single-compartment model w/ f first order elimination (proportional to concentration) → Vd remains constant o d/t binding of drug to tissue – Vd of drug may be >> than actual body Vd o Steady state Vd (central Vd + peripheral Vd): Bolus Vd >> Infusion Vd Clearence (L/min)→ volume cleared of drug per time unit, independent of concentration Drugs w/ high ER (Chapter 65): o a/w systemic CL (remove from body) and intercompartmental CL Ketamine, flumazenil, morphine, o Central CL → reflects metabolism & extraction of drug fentanyl, Sufentanil, lidocaine Elimination rate (mg/min) → amount of drug cleared per time unit, depends on concentration o Elimination ↓ over time, Clearence remains constant! o Elimination rate constant K(min¯¹)= Cl/Vd *K is for first-order elimination Extraction Ratio → fraction of inflowing drug extracted by the organ o High ER: CL ∝ Liver BF, flow-limited extraction, a/w ↑metabolism *Propofol o Low ER: CL NOT affected by BF, capacity dependent extraction, Cin ~ Cout *Alfentanil Most anesthetic drugs are cleared by hepatic metabolism EXCEPT: o Remifentanil, succinylcholine, esmolol, pancuronium *PARTIAL LIST CYP450 → oxidation, reduction, glucuronidation | non-CYP450 → conjugation, hydrolysis… Elimination kinetics o Zero-order → constant rate/amount, mg/min (50mg/min) o First-order → constant proportion, min-1 (50 %/min) ▪ Elimination rate is proportional to the amount of drug at that time ▪ When metabolism is saturated, first order can change to zero order! Multicompartment kinetics – 3 phases a/w 3 compartments o Rapid distribution → plasma to rapidly equilibrating tissues + elimination o Slow distribution → return from rapid equilibrating tissues + into slow equilibrating tissues + elimination o Elimination/terminal phase → ↓concentration d/t elimination ▪ [plasma] 2 hrs, 50% decrement time a/w infusion duration 50% decrement time - Thiopental → long (50 min) even for short infusions - Midaz, >5 hrs → Midaz >Dex - Propofol → low and constant - Fentanyl >> Alfentanil > Sufentanil >>> Remi *Fentanyl, >2hrs→ Fentanyl>alfentanil 80% decrement time - Thiopental → constant at ~8 hrs if infusion > 3 hrs - Midazolam → 2nd highest after 100 min - Dexmed → constant at ~4 hrs if infusion > 2 hrs - Propofol → gradual increase, max 150 hrs at 10 hr infusion - Fentanyl → constant at ~ 8 hrs if infusion > 2 hrs - Sufentanil → constant ~ 8 hrs if infusion > 6 hrs - Alfentanil → constant at ~ 3.5 hrs if infusion > 3 hrs # infusion >5 hrs: Fenta > Thiopental > midazolam > Dexmed > Alfentanil > Sufentanil > Propofol > Remi Hysteresis → effect time delay behind changes in plasma concentration o 2 different plasma concentrations a/w 1 drug effect OR 1 plasma concentration a/w 2 drug effects o The effect site is assumed to have a negligible volume Ke0 → rate constant for elimination of drug from effect site, determines effect rise & offset ▪ ↑ Ke0 a/w ↑ fast peak effect & rapid offset t1/2Ke0 → lag time, effect site concentration (Ce) a/w 50% probability of drug effect (C50) Sigmoid Emax relationship → concentration-effect relationship o o Hill coefficient (gamma): γ < 1 → sigmoid, γ >1 → hyperbolic Potency → a/w C50, amount of drug required to elicit effect o Left shift a/w ↑ potency o Opioid analgesia potency: Alfentanil > Remi = Fentanyl > Sufentanil Efficacy → drug effectiveness at producing event once it occupies receptor Dynamic range → concentration range of specific drug effect o Below – ineffective, Above – no additional effect o Fentanyl: analgesia → resp. depression → ↓ response to laryngoscopy → Δ EEG ED50 → dose w/ 50% probability of effect, LD50 → dose w/ 50% probability of death o Therapeutic index = LD50 / ED50 *Higher = safe Drug interactions → additive, synergistic or antagonistic Isoboles → isoeffect line for a selected probability of an effect o When dosing, choose doses a/w probability of effect ~95% Anesthetic drug interactions for hypnosis & immobility o IA + IA → additive, EXCEPT N2O o IA + IV → synergistic, EXCEPT N2O + GABA hypnotics, Sevo + GABA o IV + IV → synergistic, EXCEPT Ketamine + BZDs Opioid + IA or Opioid + hypnotic → synergistic for analgesic AND sedative effect Sedative hypnotics for ??? o Propofol + Midazolam → additive o Propofol + IA → additive Obesity a/w ↓ blood flow to adipose tissue Weight scalars o Ideal body weight (IBW) → a/w sex & height, constant → unaffected by TBW! o Lean body mass (LBW) → adjusts TBW to height, ↓sensitivity when TBW>127 Propofol → ↑ CL a/w increased liver volume and/or liver blood flow o TCI: ↑ propofol amount w/ ↑body weights is smaller w/ Cortinez and Eleveld models than w/ Marsh and Schnider models. Midazolam → a/w ↑Vd, no change in clearance o hepatic metabolism (=CL) is fixed, elimination longer in obese o When administering drug in a weigh-normalized fashion, the time to peak plasma concentration was the same regardless of body habitus Remifentanil → Vd & CL similar in lean and obese pts o FFM similar to TBWlean | LBM – significant underdosing, NOT good for infusion Inhaled anesthetics → NO PROOF that they accumulate in obese o Time to 63% equilibrium w/ adipose tissue: Desflurane >22 hrs, Isoflurane >35 hrs CT ) אתה זז? צריךlean=( לאין Propofol: Bolus – LBM, infusion – TBW or CBW דיאליתI רופהT מידזולם Midazolam: Bolus – TBW, Infusion – IBW וטליתT רופהT דקס Dexmedetomidine: TBW !LBM רמי – לא Remifentanil: do NOT use LBM (significant underdosing) NO need to adjust = MO Morphine: weight- based dosing NOT necessary Elderly pts a/w ↓dose requirements w/ pharmacodynamic & pharmacokinetic changes o 80 vs. 20 y/o: Remi: ↓ 55% | Propofol: ↓ 65% Mechanisms: ↓CO causing slower distribution, ↑ peak concentration, ↓ clearance, ↓ Vd Chapter 19 – inhaled anesthetics – mechanisms of action Molecular structures o Halothane, Isoflurane, Desflurane, F3 → contain chiral carbon, exist in 2 enantiomers o F6 (amnestic non-anesthetic non-immobilizer) → 2 chiral carbons, exists in 2 trans & 1 cis enantiomers Meyer-Overton correlation → anesthetic potency is related to the lipid-water partition coefficient o Lipid-centered explanations (anesthetics affect the cellular lipid bi-layer changed to protein-centered mechanisms (proteins as molecular targets of anesthetic effect) MAC (vol% )→ IA atmospheric pressure required to prevent movement in response to stimuli in 50% pts o 1 MAC ~ IV EC50 (NOT ED50) | Coma-like state a/w 1.3 * MAC ~ IV EC95 IA – anesthetic effect: o Amnesia → most sensitive end point (1/4 MAC); hippocampus, amygdala o ↓ LOC → sensitive (1/2 MAC); cortex and thalamus o Immobility → less sensitive (1 MAC); spinal cord o Cardiovascular responses → least sensitive, a/w high MAC Immobility o Effect at spinal level→ a/w Glycine, the primary inhibitory NT in spine ▪ NOT a/w GABAA or nACh receptors | Potassium (K2P) channels might play a role ▪ Intrathecal Na+ channel inhibitor → potentiates anesthetic immobility (↓MAC required for immobility) o a/w suppression of the pain withdrawal reflex arc Unconsciousness o Level of consciousness a/w “bottom-up” processes; content of consciousness a/w “top-down” processes ▪ Anesthetics suppress descending >> ascending neural connectivity → a/w breakdown of cortical connectivity and processing. Amnesia o Explicit memory inhibited at lower concentrations of IA than implicit memory (=”impossible to recall”) o Inhibition of hippocampus-dependent learning a/w impairment of explicit memory Sedation o Effect may be a/w stimulation of sleep-promoting nuclei o Sedative effect of N2O & Xenon → a/w NMDA receptor antagonism and K2P activation, NOT a/w GABA IA bind proteins in hydrophobic cavities w/ an element of amphiphilicity (polar & nonpolar features) o Binding a/w weak hydrogen bonds, nonpolar vander Waals interactions, and a polarizing effect o Different drugs may bind in different orientations with a single amphiphilic cavity or occupy different cavities GABAA and glycine receptor function → Inhibitory Cl- channels o GABAA → neocortex and allocortex, GlyR → spinal cord o GABA α1 subunit → a/w the sedative and amnesic effect, but NOT anxiolysis, of BZDs o GABA γ subunit → required for BZD and IA effect | GABA transmembrane domains 2 + 3 → critical for IA 5HT3 Receptors → CNS cation receptor a/w emetogenic properties of IA nnAChR → Presynaptic excitatory cation channels *a/w amnestic effect NMDA Receptors → Postsynaptic excitatory glutamate channel o Channel opening requires presynaptic agonist stimulation for transmitter release AND postsynaptic depolarization (relieves voltage-dependent block by Mg) *serve as coincidence detectors o Non-NMDA receptors: AMPA receptors → weakly inhibited by IA | Kainate receptors → enhanced by IA **NOTE: NMDA, AMPA, Kainate → receptors a/w excitatory postsynaptic depolarization, but blocked by IA mainly via a presynaptic mechanism. *VA → presynaptic blockade, N2O + Xenon → postsynaptic block Na+ channels → axonal channels inhibited by IA to ↓conduction o ↓Preterminal AP a/w ↓postsynaptic response | Occurs after channel gating via 2 drug binding sites Ca+ channels → presynaptic inhibition by IA a/w ↓excitatory transmission o T-type channels (low voltage-activated) → particularly sensitive to VA and N2O o L-type channels (high voltage-activated) inhibited by IA in cardiomyocytes → a/w negative inotropic effect ▪ Xenon does NOT affect myocardial function | a/w malignant hyperthermia (RyR1-CaV1.1 interaction) K Channels → crucial for repolarization after AP, thus determine excitability and AP duration + o KIR, KV, Ca-activated K channels → INsensitive to IA & Xenon | KATP → activated by IA & Xenon (see below) o HCN channels → a/w If in cardiac pacemaker cells, inhibited by VA → a/w ↓bursting frequency G protein-coupled receptors (GPCR) → regulate downstream effectors to control secondary messengers (Ca+2) o Directly affected by IA, can effect anesthetic sensitivity (↓MAC) Intracellular protein phosphorylation → PKC is a/w regulation of many ion channels and receptors o Halothane & Sevoflurane → ↑PKC activity | PKC is NOT a/w VA immobilization o VA & Xenon a/w cardioprotective & neuroprotective effects via activation of multiple GPCR and protein kinases, targeting downstream sarcolemmal and/or mitochondrial KATP channels o Isoflurane, Propofol & Ketamine → a/w ↓ phosphorylation of sites on NMDA and AMPA glutatmate receptors to ↓ excitatory glutamatergic synaptic transmission IAs affect epigenetic mechanisms a/w DNA-binding histone proteins Neuronal excitability is determined by resting membrane potential, AP threshold, and input resistance o GABAA receptors in extrasynaptic sites influence excitability IA a/w ↑ inhibitory and ↓ excitatory transmission ➔ overall inhibitory effect o Inhibition → a/w GABA, pre- & post- & extra-synaptic mechanisms o Excitation → a/w Glutamate; pre- & post-synaptic mechanisms ▪ NMDA inhibition: Volatile IA – mainly presynaptic, non-halogenated IA (Xenon, N2O) → mainly postsynaptic VAs effect synaptic transmission in multiple locations o Presynaptic → ↑ basal GABA release, ↓glutamate release o Postsynaptic → potentiating GABA- and glycine-activated ion channels, inhibiting glutamate-activated channels o Extrasynaptic → enhancing GABA receptors Non-halogenated IA (Xenon, N2O, cyclopropane) → post >> pre minimal effect on inhibitory current ↓ excitatory current (primarily postsynaptic) Volatile anesthetics → pre- & post- & extra ↑ Inhibitory current (GABA, pre & post & extra) ↓ excitatory current (primarily presynaptic) LTP → model of learning and memory a/w glutamatergic excitatory connections o Halothane, enflurane, isoflurane → do NOT block LTP in vivo | Ketamine, CPP (anti-NDMA) → block in vivo o Note: Isoflurane blocks LTP in vitro, but NOT in vivo! Reason unknown IA a/w ↓ Spontaneous neuronal activity *GABAA receptor-dependent Delta (δ)-rhythms → 1.5-4 Hz, a/w deep sleep and GA o δ – α phase changes → “signature” of propofol induced unconsciousness Theta (ϴ)-rhythms → 4-8 Hz, signals the “online state” o Type I (atropine-resistant) → affected by Isoflurane, a/w anesthetic-induced amnesia o Type II (atropine-sensitive) → evoked under anesthesia, slowed and potentiated by Halothane Gamma (γ)-rhythms: slow γ (30-50 Hz), γ (50-90 Hz), fast γ/ε rhythm (>90 Hz) o Frequency depends on decay of GABAA receptor-mediated inhibitory synaptic currents TREK-1 (gene for two-pore domain K+ channels (K2P)) → resistant to all VA Chapter 20 – Inhaled anesthetics: uptake, distribution, metabolism, and toxicity Partial pressure = portion of total pressure contributed by one component of a gas mixture o PIA determines its pharmacologic effect o Measured at 1 ATM → ↑Altitude (↓PATM) a/w ↑ pharmacologic effect because the PIA is lower Vapor pressure = partial pressure of a VA within the drug reservoir, agent-specific & ↑ VP w/ ↑temp ° o VAs = PP < 1 ATM @ 20 ℃ & boiling point > 20℃ | Gaseous anesthetics = PP >1 ATM @ 20 ℃ & boiling point >20℃ Partition coefficient (λ)= measure of hydrophobicity / lipophilicity o High oil/gas coefficient (λ) = Hydrophobic compound = High solubility = ↑ potency (low %vol for MACimmobility) ▪ λ ∝ Hydrophobicity ∝ Solubility ∝ Potency | ↑ λ a/w rapid uptake but slow rise in Palv o ↑ Blood solubility w/ ↓ temp°, fatty food | ↓ Blood solubility w/ anemia, malnutrition - λB/G: Des < N2O < Sevo < Iso < Enflur < Halo < Methoxy (“Doctors Never Say It’s Easy, However - Money!”) - Nothing special about Enflurane & Isoflurane - Halothane is most dense - Sevo is heaviest *SEVen times heavier! - Desflurane: most potent of all IA, low boiling point so high vapor pressure - Vapor pressure: N2O >>>> DES >>Halo>methoxy - N2O → lowest in everything EXCEPT vapor pressure & MACimmobility – highest! Equilibration between vaporizer and circuit Anesthetic delivery from the vaporizer (VAdel) in L/min = Pdelivered · FGF · t Fresh gas wash-in of the breathing circuit is by bulk flow and mixing, INdependent of the gas exchange process o Depends on FGF, )Pdel – Pcirc(, and inversely related to Vcirc o Time constant τ = Vcirc / FGF → represents time to Pcirc = Pdel ▪ Each τ represents a 63.1% decrease in fraction of old gas 100 → 37 → 14 → 5 → 2% ▪ T1/2 (time for halving the vaporizer-circuit concentration difference) = 0.693 · τ Breathing circuit component effect rate of equilibration between vaporizer and circuit o Hydrophobic VAs (Halothane) → absorb more into circuit components | low-solubility VAs → negligible effect Rate of anesthetic exchange between circuit and lungs depends on MV and total pulmonary air space Rebreathing depends on balance between FGF (in) and MV (out) Anesthetic uptake is a/w pulmonary blood flow, IA solubility and PP gradient Anesthetic induction/emergence is a/w rate of change in Palv o Rapid ↑ Palv/ Pcirc is a/w: ↑ V̇ alv , ↓ Q̇ , ↓ λ o Open circuits a/w fast Δ Palv d/t low circuit volume & high FGF o Fastest: Desflurane (↓λ), Slowest: Enflurane (↑λ) ↑ pulmonary dead space → a/w ↓ anesthetic uptake o Strongest effect w/ high FGF + low solubility agent * Alveolar ventilation becomes limiting factor in uptake R → L shunt a/w accelerated rise in Palv d/t blood bypassing lungs and less IA removed from pulmonary gases o Rapid ↑ Palv d/t ↓ anaesthetic uptake into blood (↓ uptake d/t ↓ Q >> ↑ΔP(alv-mv)) o The shunt effect on Part (a/w anesthetic uptake into tissues) vs. Palv is larger for insoluble IAs (N2O) L→ R shunt a/w ↑ Pmixed venous that slows uptake (lower alveoli-blood gradient) Concentration effect → rapid gas uptake results in smaller relative decrease in alveolar [IA] o When gas is a large % of gas mixture: rapid uptake a/w ↓ alveolar volume → maintains Palv of IA 2 gas effect → rapid N2O uptake maintains PIA and increases PO2 nd o ↓ alveolar volume ➔ ↑ uptake of VA & O2 | ↑ effective MV d/t air being “pulled in” VA uptake into tissues: ** blood volume → 7% of body mass 1. Vessel rich group → heart, brain, lungs. 10% of body mass, but 70% of CO 2. Skeletal muscle → 40% of body mass, 10-15% of CO (20cc/kg/min) 3. Fat → > PCNS) w/ high FGF (>6 LPM) → a/w high waste of IA (low soluble > high solubility IA) Closed-circuit anesthesia → allow the use of FGF Isoflurane > Desflurane *NOT Sevo o IA oxidation a/w metabolites that may modify hepatic proteins and induce hepatitis o Metabolites after Halothane, Isoflurane, and desflurane – identical ; Enflurane – immunologically similar o NOT a/w Sevoflurane!! Highest extent of tissue metabolism of VAs, but metabolites do NOT interact w/ liver Fluoride-associated nephrotoxicity → ONLY w/ Methoxyflurane! o Nephrotoxic threshold for serum F- >50 μM → a/w renal dysfunction and ↑ mortality o Postanesthesia ↑ F-: Methoxyflurane >>> Sevoflurane > Enflurane >> Isoflurane > Desflurane o Effect NOT a/w peak or duration of high F- concentration o Methoxyflurane anesthesia(2-3 hrs) → end of surgery < 50, fluoride peak (~60) POD 2-3, slightly elevated > 1 week Sevoflurane - MOST tissue metabolism of VAs (5%), but only VA to NOT be a/w immune-mediated hepatitis - HIGHEST F- metabolite (a/w nephrotoxicity) of VAs * Postanesthesia ↑ F- a/w extent of tissue metabolism ( S > E > I > D) * NO clinically significant nephrotoxicity (ONLY methoxyflurane) - Compound A → nephrotoxic in animals, NOT a/w significant nephrotoxicity in humans * ↑ risk: FGF < 2 L/min, Sodalime & Baralyme CO2 absorbents Compound A → a/w nephrotoxicity in rats, NOT humans o By itself not nephrotoxic, but undergoes metabolism by β- lyase activity to form TAF that is toxic ▪ Humans have less β- lyase, a/w lack of toxicity + interspecies metabolism and PCT sensitivity differences o Sevoflurane a/w ↑ compound A WITHOUT clinically significant nephrotoxicity in humans ▪ a/w certain CO2 absorbents (Soda lime & Baralyme) | ↓ risk w/ FGF > 2 L/min - Strong bases a/w ↑CO production: KOH > NaOH > BA [OH]2 > Ca [OH]2 CO KnockOut! - CO production: Baralyme > Soda lime, and w/ higher H20% production threshold (5 vs. 1.4%) B closer to CO than S - VA & CO: Desflurane > Enflurane > Isoflurane “COol Kids Do Ecstasy Inside” - LiOH → single base, lowest water% Carbon monoxide production → a/w strong dry CO2 absorbents o Desflurane > Enflurane > Isoflurane o a/w ↓↓ moisture of CO2 absorbent d/t “flushing” of breathing circuit for 1-2 days o ↑ CO production a/w: IA (D>E>I), absorbent (baralyme> soda lime), ↑ temperature, ↓FGF ▪ CO production observed when water content falls below: soda lime → 1.4%, Baralyme → 5% o CO production correlates w/ anesthetic concentration in circuit and INVERSELY CORRELATES w/ FGF Heat production → a/w VA degradation by CO2 absorbents exothermic reaction o Sevoflurane produced the most heat when use w/ desiccated CO2 absorbent N2O toxicity o N2O irreversibly inhibits Methionine synthase → ↓ Vitamin B12 ▪ Vit B12 Deficiency a/w Pernicious anemia → megaloblastic anemia w/ subacute myelopathy & neuropathy ▪ Megaloblastic bone marrow changes after N2O exposure of >12 hrs in healthy or 2-6 hrs in critically ill o Long-term N2O exposure a/w: ↓B12, megaloblastic anemia, myelopathy, neuropathy, encephalopathy o N2O a/w ↑ homocysteine but W/O altering cardiovascular morbidity ▪ Preop infusion of B12 or folate DO NOT prevent normal elevation in homocysteine Anesthetic exposure >4hrs in children > Desflurane (10) > Iso, Sevo - Ozone-depleting potential: Halothane highest Makes Hole (“halo”) In ozone Sevoflurane & Desflurane – 0! - Global warming potential: Desflurane highest, N2O lowest Damn it’s hot! NO correlation between adverse health effects & exposure to anaesthetic gases, W/ or W/O a scavenging system. NO evidence of harm to fetuses of women anesthetized while pregnant Exposure: o Halogenated agent: AVOID >2 ppm for > 1 hr | N2O: AVOID > 25 ppm over 8 hrs Xenon o ONLY IA that is not an environmental pollutant o Very low solubility in blood (λb/g = 0.14) ➔ rapid onset and emergence | MACimmobility 0.61 ATM o Cardioprotective & neuro protective | minimal CV depression | Analgesic activity o Higher density than N2O or air → a/w ↑ flow resistance and WOB | ↑ PONV | a/w expansion of air spaces o NO biotransformation or reactions w/ CO2 absorbents | NO malignant hyperthermia o DOES NOT improve neurocognitive function or survival Chapter 21 – pulmonary pharmacology and inhaled anesthetics Asthmatics → 9% w/ perioperative bronchospasm | 25% w/ wheezing after induction | 1.7% poor resp outcome o Acute bronchospasm → may occur at any stage WITHOUT prior hx of asthma or COPD ↑ AW resistance a/w ↑bronchial smooth muscle tone d/t cholinergic stimulation via mAChR o Ganglionic M1 → facilitate neurotransmission o Neuronal M2 → presynaptic, ↓ ACh release (negative feedback) | ASM M2 → counteract AW muscle relaxation o ASM M3 → airway smooth muscle contraction in response to ACh BSM contraction a/w ↑ [ICa+2] & ↑Ca+2 influx, stimulated by stretch-activated receptors, adenosine, ↑ local Na+ Histamine stimulation of H1 receptors on BSM ➔ ↑PKC activating ➔ ↑ [ICa+2] ➔ bronchoconstriction (↑RL, ↓Cdyn) o VAs inhibit effect of histamine on pulmonary resistance and compliance (RL, Cdyn) ➔ bronchodilation Respiratory epithelium directly modulates BSM tone * Crucial for VA-induced bronchodilation (see below) o Removal of epithelium ↑↑ contractile responses to ACh & histamine in large AW All VAs cause concentration-dependent bronchodilation → Distal > proximal ***, Bronchioles > bronchi o indirectly attributed to ↑ PCO2 tension (Isoflurane blocks hypercapnia-induced bronchodilation) o VAs DO NOT directly alter RL & Cdyn BUT they attenuate their response to histamine o Attenuated by intraoperative hypothermia o Halothane – most effective bronchodilator ** Halothane >> Iso=En=Sevo All VAs a/w increased ↑ Gas density at higher MACs➔ ↑ AW resistance, increases w/ high MAC o Desflurane – highest increase in resistance @ MAC 2, ↑ total inspiratory resistance by 26% All VAs a/w ↓ respiratory system resistance, EXCEPT Desflurane that may ↑R o ↓ Resistance: Sevoflurane > Halothane > Isoflurane o “Ceiling effect” → a/w decreased effect of VAs on very distal bronchioles o AVOID Desflurane in pts w/ reactive AW disease or children w/ AW susceptibility (asthma, URTI) → a/w ↑↑ AW resistance & may worsen bronchoconstriction in noradrenergic noncholinergic activation by tachykinins All VAs a/w ↑ work of breathing, EXCEPT Sevoflurane a/w ↓WOB β-agonist effect for acute bronchospasm → beneficial ONLY w/ halothane Sevoflurane → best VA for asthma tx - Decreases resistance the most - Decreases WOB (unique) VAs a/w ↓ airway smooth muscle contractility - Decreases ciliary function the least o Direct effect on bronchial epithelium and ASM cells - LEAST irritating to AW ▪ ↓cAMP ➔ ↓ intracellular Ca+2 by efflux + ↑ SR uptake ➔ bronchodilation ▪ a/w inhibition of dose-dependent inhibit of voltage-dependent Ca+2 channels VAs inhibit T-type VDC (bronchus) > L-type (trachea+bronchus) ➔ bronchodilation in distal > proximal AW o Indirect effect by ↓reflex neural pathways ▪ Brainstem GABAA and lung GABAB receptors | Modulation of pre & postjunctional AW cholinergic n. VA bronchodilator effect is dependent on the presence of bronchial epithelium o ↓ response w/ epithelial damage or inflammation (i.e. asthma) *** VA a/w bronchodilation in distal > proximal EXCEPT chronic reactive AW disease where d/t epithelial inflammation, proximal > distal! Metachronism → coordination of cilia movement (rapid cephalad stroke → slow caudal stroke) o ↑temp a/w ↑ ciliary motility | ATP-dependent cycle | complex drug-drug interactions o Impaired mucociliary function ∝ low levels of nasal NO VAs cause concentration-dependent ↓ in mucous clearance o Sevoflurane → weakest cilioinhibitory effect o a/w ↓ciliary beat frequency, disrupting metachronism, Δ in quality or quantity of mucous o additional factors: ↑FiO2, ET tube presence, PPV, medications (steroids, atropine, β-antagonists) Normal bronchial mucous transport: 10 mm/min *↓ of > 3.5 mm/min → ↑ pulmonary complications Halothane & Isoflurane → a/w impaired surfactant synthesis during a 4hr exposure o a/w ↓Na/K-ATPase & Na channel activity in alveolar type II cells ➔ ↓ phosphatidycholine and alveolar edema ↑PVR d/t pulmonary vasoconstriction a/w hypercarbia, hypoxia, and acidosis o Hypoxia & acidosis → synergistic | additional factors: large tidal volume, high PEEP, critical closing pressure NO synthase – isoforms: neuronal (nNOS), vascular (eNOS), and calcium-independent (iNOS) o All widely distributed in lung | NO interacts w/ iron➔↑cGMP➔relaxation of vascular and nonvascular muscles o NO - ↑ cGMP | Prostacyclin - ↑ cAMP | Sildenafil & Tadalafil - ↑ cGMP HPV → unique because other vascular beds (coronary and cerebral) dilate in response to hypoxia o Trigger: alveolar P02 < 60 mmHg, maximal when ~ 30 mmHg o a/w ↑ Ca+2 release from SR, ↑ Ca+2 sensitization, & modulation of K+ channels in smooth muscles o Does NOT contribute to V/Q mismatch in normal conditions. All VAs dilate the pulmonary vascular bed, a/w ↓PVR o ↑ vasodilatory response of VA a/w ↓SR Ca+2 stores (neonates) or ↓ protein kinase activity (primary PuHTN) Concentration-dependent HPV-inhibition: Halothane > Desflurane (@ 1 MAC) o HPV inhibition potency: Halothane > Enflurane > Isoflurane HEI o Sevoflurane-induced ↓HPV is unique → NOT a/w voltage-sensitive K+ channels o Anesthetic-induced inhibition is NOT dependent on pulmonary vascular endothelium or NO o VA + CCB ➔ further reduced HPV by 40%, suggesting different mechanisms of HPV inhibition One lung ventilation → minimal effect on PaO2 & shunt% is similar between IV vs. IA Central respiratory pattern generator → several nuclei in medulla & pons o Lateral hypothalamus (midbrain) → wakefulness drive o Nucleus tractus solitarii (medulla) inhibits the ventral respiratory group ➔ a/w ↓ firing of phrenic and expiratory motor neurons Chemoreceptors maintain ventilatory response: central (2/3) > peripheral (1/3) o Central → senses ↓ [pH] /↑ [H+] | Peripheral → sense hypercarbia & hypoxia Respiratory drive is suppressed by all IA, EXCEPT N2O o Eliminate wakefulness drive ➔ dose-dependent suppression of conscious breathing drive o Peripheral chemodrive MORE DEPRESSED than central chemodrive o Upper AW motoneurons MORE DEPRESSED than inspiratory motoneurons @ MAC > 1 → dose-dependent ↓ MV d/t ↓ Tv *[↓TV + ↑RR ➔ ↓ MV] o EXCEPT N2O → does NOT significantly reduce MV VAs a/w ↑ respiratory rate, EXCEPT Xenon Dose-dependent impairment of peripheral chemoreceptor response to hypoxia and hypercarbia o MAC 0-1 → ↓ hypoxic chemoreflexes o MAC > 1 ➔ abolishment of hypercapnic reflexes ▪ VAs a/w complete abolishment of peripheral chemoreceptors, only central chemoreceptors remain! o a/w ↑ apneic threshold (=right shift) to initiate spont. respiration Carotid body → main peripheral chemoreceptor o ↓O2 / ↑ CO2 ➔ ↑ sympathetic activity ➔ ↑ minute ventilation o HTN, OSA & CHF a/w chronically elevated carotid body afferent activity causing ↑ sympathetic tone WITHOUT affecting breathing patterns Hering-Breuer Reflex → modulates respiratory phase-timing w/ vagal mediated inhibition of inspiration a/w lung inflation and activation of pulmonary stretch receptors. o “vagal expiratory-facilitating reflex” | Active during resting ventilation in adults Neuro-mechanical components of respiratory cycle o Phrenic n. active only during inspiration with ↑ tone o Recurrent laryngeal n. → Insp – dilates glottis, Exp – constricts glottis w/ ↑subglottal pressure o Internal intercostal nerve activity ↑ only during E2 (only trace active at E2) o Medullary postinspiratory inhibitory neurons → a/w insp-exp. phase transition ▪ PI – Glycinergic neurons, E2 – GABAergic neurons VAs < 1 MAC suppress conscious control of respiratory rates o ↓ MV a/w ↓ TV > ↓ RR o VAs a/w ↑ RR a/w ↓ inspiration & ↓ exhalation | Opioid a/w ↓ RR d/t ↑ expiratory duration Hypoxic ventilatory response → ↑ respiratory drive w/ ↓ PaO2 o Seen in tunnel workers & climbers at high altitude HVR inhibition: “Hypoxic Elephants Sing In Delight” o MAC < 1 → impaired | Halothane MAC > 1.1 → abolished o HVR suppression potency: Halothane > Enflurane > Sevoflurane > Isoflurane > Desflurane ▪ a/w inhibition of peripheral chemoreflexes | NOT restored by pain or CNS arousal Diaphragmatic function – preserved, inspiratory rib cage muscles – depressed! o depression of ribcage muscles >> abdominal diaphragmatic muscles VAs @ MAC > 1-1.3 a/w abolishment of defensive AW reflex BUT may be enhanced and prolonged under lower concentrations of VAs *a/w laryngospasm at low VA concentrations AW irritation: Desflurane and Isoflurane – most irritating, Sevoflurane - least Sepsis-induced acute lung injury o ↑ NO production causing ↑cGMP a/w myocardial depression and circulatory shock o VAs → anti-inflammatory effect by ↓ cytokine production, ↓pulmonary edema, ↓ PMN migration VAs are a/w ↓ lung injury d/t mechanical ventilation, EXCEPT Desflurane Sevoflurane & Isoflurane → a/w ↓ lung injury w/ ALI, VILI and lung re-perfusion injury Factors affecting VA washout: solubility, FGF, MValveolar, CO o To avoid rebreathing → FGF should be > peak inspiratory flow rate FA/FI ratio → reflects uptake. Fastest: Xenon > N2O, Slowest - Halothane N2O & Xenon have low solubility ➔ rapid rise in FA/FI ➔ fast onset and offset of anesthesia o Solubility Xenon > N2O | both inhibit NMDA receptors N2O is hemodynamically stable → enhances catecholamine release and does NOT ↓SVR or CO Analgesic effect: 66-70% N2O = Remifentanil whole blood concentration of 2 ng/mL o Sevoflurane ↓ analgesic potency of N2O o Reversed by Naloxone (= μ opioid receptor mediated) | Tolerance to N2O within 40 minutes 15-20 minutes of N2O during emergence is NOT a/w clinically relevant bowel dilation N2O-related PONV is clinically INSIGNIFICANT when exposure < 1 hr * incidence ∝ duration of N2O exposure N2O NOT a/w adverse effects on pHTN or RV function | NO ↑ death or CV complications (ENIGMA II) Xenon → sedative effect via NMDA receptor inhibition in the CNS * MAC = 63.1% a/w faster emergence (by 4 minutes) but NO reduction in length of PACU or LOS stable intraoperative hemodynamic response → maintains BP & ↓ HR Potent 5-HT3 antagonist → antiemetic effect | ↑ PONV same as other IA Unlike N2O: o NO gas expansion | NO diffusion hypoxia | ↓ RR (vs. no affect) | NO tolerance High density and viscosity ➔ ↑ airway resistance that is NOT a/w bronchoconstriction All VAs a/w ↑ work of breathing, EXCEPT Sevoflurane All VAs a/w ↑ respiratory rate, EXCEPT Xenon All VAs a/w ↓ Tidal volume, EXCEPT Xenon VAs a/w dose-dependent ↓ MV (↓TV + ↑RR), EXCEPT: - N2O → does NOT ↓ MV All VAs a/w ↓ res
