Blood disorders Reduced Flashcards
1
Q
What are some questions you might want to ask in regards to hematology?
A
- Have you ever had a blood problem?
- Anemia? Leukemia?
- Any clotting problems?
- Lots of bleeding from cuts, nosebleeds, surgery, dental work?
- Have you ever required a blood transfusion?
- Has a family member/blood relative ever had a serious bleeding condition or clotting problem?
2
Q
What common medications would make you concerned in terms of possible hematological problems?
A
- Aspirin/NSAIDS
- Vitamin E,
- Ginseng, Gingko, Garlic, Saw Palmetto.
- How often, how much, and last dose?
3
Q
Anemia Pathology
A
- Can be either Acute or Chronic
- Acute = Acute blood loss
- Chronic = Nutritional Hemolytic, Aplastic, Manifestation of another disease, Abnormal RBC structure (Sickle cell, Thalassemia)
-
Disease state related to
- abnormal low concentration of hemoglobin (RBCs)
- Abnormal structure of hemoglobin
-
Clinical manifestation of decreased oxygen carrying capacity and delivery
- Hemoglobin Defines oxygen carrying capacity
- Anemia decreases o2 carrying capacity
- Care must inclued treatment of the underlying disease as well as the state of anemia
- MUST avoid disruption of compensatory mecheanisms
4
Q
Calculation of arterial blood oxygen content
A
CaO2 = (Hgb x 1.39) SaO2 + PaO2 (0.003)
- 1.39 = O2 bound to hemoglobin
- SaO2 = saturation of hemoglobin with O2
- PaO2 = arterial partial pressure of oxygen
- 0.003 = dissolved oxygen ml/mmHg/dl
- Normal O2 capacity = 16-20 mL/dL
5
Q
Compensatory mechanisms for anemia
A
- Increase CO
- Increase 2,3-DPG
- Increased P50
- Increase plasma volume
- Decreased blood viscosity = increased CO
- Decreased SVR
- Blood shunting to organs with higher extraction ratios
- Kidneys release EPO
- RIGHTWARD shift in ox-hem disassociation curve
6
Q
Oxyhemoglobin disassociation curve shifts to the right with:
A
Think of anything that increases metabolism → RBC will want to drop off Oxygen at the tissues
- Increased CO
- Acidosis = Decreased pH
- Increased 2-3 DPG
- Exercise
- Increased temeperature (sepsis)
- Hgb variants with decreased oxygen affinity (Sickle cell)
*
7
Q
Oxyhemoglobin disassociation curve shifts to the left with:
A
Think anything that decreases metabolism →tissue does not need as much oxygen
- Decreased CO2
- Alkalosis = Increased pH
- Decreased 2/3 DPG
- Decreased temperature - hypothermia
- High oxygen affinity Hgb variants (Fetal Hgb)
(a leftward shift on someone that is dependent on a rightowrd shift may be a problem - we do this from hyperventilation and decreaseing temperature)
8
Q
Changes that could interefere with oxygen delivery to the tissues
A
- Decreased CO
-
LEFTWARD shft in oxy-heme disassociation curve
-
Respiratory alkalosis
- hyperventilation/decreased PaCO2
- Hypothermia
- Abnormal Hgb such as fetal hemoglobin and carboxyhemoglobin
-
Respiratory alkalosis
9
Q
Anemia Basic Anesthetic management
A
- Know your pts preoperative Hgb and HCT
- anemia suspected if hemoglobin
- < 11.5 g/dl (females)
- < 12.5 g/dl (males)
- anemia suspected if hemoglobin
- Hgb and HCT are RELATIVE measuremants
Treating the underlying cause
10
Q
Anesthesia management and considerations for chronic anemia
A
Goal = AVOID disruptions of compensatory mechhanisms that are aimed at maintinging O2 delivery to the tissues!
- Indentify and treat underlying disease if possible
- Maximize O2 delivery- High FiO2
-
Avoid drug induced decreases in CO
- consider etomidate induction
- may want to use high opioid technique
- hydrate/avoid hypovolemia
- AVOID propofol, high amounts of IAs, STP
-
AVOID leftward shifts of the oxyhemoglobin disassociation curve
- no hyperventilation/respiratory alkalosis
- no hypothermia
-
Consder volitile anesthetics may be LESS soluble in plasma
- may have a faster induction, however, often OFFSET by the fact that these patients have and increased CO
11
Q
Anemia and the decision to transfuse
A
Goal of transfusion therapy = Increase O2 carrying capacity and/or correct a coagulation disorder
- There is NO tranfusion trigger and the decision to transfuse is based on:
- The clinical judgment that the oxygen carrying capacity MUST be increased to prevent oxygenconsumtion(VO2) from being greater thanoxygendelivery (DO2)
- A drop in Hgb from 15 to 10 = 33% decrease in arterial oxygen content!
- it is also manifested by a RIGHT shift in the poxthemoglobin disassociation curve
12
Q
2006 ASA guidelines regurding blood transfusion
A
- Rarely indicated if Hgb > 10 g/dL
- Almost ALWAYS indicated if Hgb < 6 g/dL
- If Hgb is 6-10: transfusion is based on the patients risk for complication and inadequate oxygenation
- Use of a transfusion trigger of Hgb is NOT RECOMMENDED
- Where apprropriate use of autologous blood, cell save or acute normovolemic hemodilution and measures to decrease blood loss (deliberate hypotension)
- Indications for transfusion are more liberal for autologous blood than blood from the blood bank
13
Q
How do you know when to transfuse?
A
- You calculate the allowable blood loss for your surgical case
- ABL = EBV x (patients Hct - Allowable Hct)
patients Hct
- Know that:
- 1 unit of RBCs will increase Hct 3-5%;
- or it will increase Hgb ~1 g/dL
14
Q
Nutritional anemias
A
- Iron deficiency
- Folic acid deficiency
- B12 deficiency
- Chronic illness (infections, cancer, RF, DM, AIDS, connective tissue disorders)
15
Q
Iron deficiency anemia- RBCs are? Common causes in adults?
A
- Nutritional Anemia
- Ineffective erythropoesis and Microcytic RBCs
- In adults, depletion of iron stores is caused by chronic blood loss
- GI bleed
- menorrhagia
- cancer
- Most common form of nutritional anemia in infants and children
16
Q
B12-def. anemia - RBCs are? May result in? Anesthesia considerations?
A
Macrocytic (Megaloblastic bone marrow morphology)
B12 deficiency may result in pernicious anemia
- Bilateral peripheral neuropathy
- Loss of proprioception/vibratory sensation in lower limbs
- Decreased deep tendon reflexes
- Unsteady gait
- Memory impairment/mental depression
Anesthesia considerations:
- Avoid regional blocks (neuropathys)
- Avoid N2O (binds B12)
- Maintain oxygenation
- Emergency correction for imminent surgery is RBC transfusion
17
Q
Causes hemolytic anemias
A
Acquired Hemolytic Anemias
- Drug induced (High dose PCN, alpha- methyldopa)
- Disease/infection induced (malaria, epsteen Barr)
- Sensitization of RBCs (Maternal/fetal)
(particals released durring hemolysis can result in DIC and hypersplenism)
Hereditary hemolytic anemias
- Hereditary spherocytosis
- Paroxysmal nocturnal hemoglobinuria
- Glucose 6 Phospahete dihydrogenase deficiency
- Pyruvate Kinase Deficiency
18
Q
Folic acid deficiency anemia- RBCs are? May result in? Anesthesia considerations?
A
Macrocytic (Megaloblastic bone marrow morphology)
Folic acid deficiency may result in penicious anemia
- Smooth tongue (difficult intubation)
- Hyperpigmentation
- Mental depression
- Peripheral edema
- Liver dysfunction
- Severely ill patient
Anesthesia considerations:
- Thorough airway assessment
- Have an alternative airway plan in place
- often have difficult airways d/t tongue texture!
19
Q
Glucose-6-Phosphate dehydrogenase deficiency What is it? Who does it affect? What should you avoid?
A
Form of hemolytic anemia
- Most common enzymopathy; decreased G6PD activity leaves RBCs susceptible to damage by oxidation.
- Cell membranes have increased rigidity of membranes and there is accelrated RBC clearance
- Acute and chronic episodes.
- Most prevalent in: Blacks, Asians, Mediterranean populations
Anesestetic consideratons:
- AVOID: oxidative drugs (LAs, Benzos, Meth. Blue)
- AVOID: hypothermia, acidosis, hyperglycemia, infection
20
Q
Peri-op risks and concerns for hemolytic anemia
A
Hemolytic anemia risks:
- Increased tissue hypoxia
- Increased infection risk if prior splenectomy
- Increased risk of venous thrombosis
To offset these risks preop planning should include:
- EPO given for 3 days pre-op
- Consider for transfusion if:
- Hgb acutely < 8 g/dL or
- Hgb chronically < 6 g/dL
- Adequate pre-op hydration and prophylactic RBC transfusions
- Caution with Methylene Blue - can increase hemolysis!!!
21
Q
Sickle cell anemia patho
A
Cellular Pathology
- Inherited Single AA defect in the ß-globin chains
- Mutant S hemoglobin →valine substituted for a glutamic acid
- Hgb aggregates & forms polymers when there is low O2 concentrations
- Hemoglobin S has a shorter life span
Sickle cell trait vs. disease
- trait = heterozygus carriers (asymptomatic)
- disease = Homozygus (have the disease)
22
Q
Explain a Sickle cell crisis
A
- Life threatening
- Acute vaso-occlusive crisis (Deoxygenation causes Hgb S to form insoluble globulin polymers)
- Ischemia and organ infarcts
- very painful
- Can cause stroke, renal failure, liver failure, splenic sequestration, PE and acute chest syndrome
23
Q
Periop planning for Sickle cell anemia
A
- O2
- 12 hours hydration
- Pre-op exchange transfusons (HCT to 30% Hgb S <30%)
-
Caution with pre-med
- avoid respiratory depression that can lead to acidosis
- USE Regional!
- AGGRESSIVE pain management
- Strict aseptic technique, must avoid infections
- Avoid tourniquets
AVOID ALL SITUATIONS LEADING TO
- Hypoxemia
- Hypovolemia
- Stasis
24
Q
What are the signs and symptoms of acute chest syndrome and how is it managed?
A
Signs and symptoms of acute chest syndrome due to pumonary vascular occlusion
- Pleuritic chest pain
- dyspnea
- fever
- acute pulmonary HTN
Treatment:
- Transfuse to Hct 30%
- give oxygen
- antibiotics
- inhaled bronchodilators
- aggressive pain management
25
Thalassemia major patho and signs and symptoms
* **Inability to form alpah or beta-globin hemoglobin chains**
**Signs and symptoms:**
* Hepatosplenomegaly
* Dyspnea &orthopnea
* Infection risk
* CHF, dysrhythmias
* **Bone malformations** (Overgrown maxillae - difficult intubation!!!)
* Hemothorax
* **Spinal compression** (No epidurals or spinals)
* Mental Retardation
* Digitalis sensitivity
* Increased RBC production
* Jaundice
* Iron overload
26
thalassemia
Perioperative risks and concerns
1. **Difficult airway** (maxillary deformities), consider awake fiber optic
2. **Complications of iron loading** d/t chronic therapy
1. ****Arrythmias, CHF, Right heart failure, cardiomyopathy
* Get an **EKG** and **ECHO**
* also note: **VERY** sensitive to the effects of **digitalis**
2. Adrenal Insufficiency
* Decreased vasopressor response
3. Hemodynamic comprimise with induction agents
* if low cardiac reserve use cardiac sparing drugs
4. **Diabetes** → monitor blood glucose
5. **Liver Dysfunction→** coagulopathy
* **AVOID regional**
6. **Hepatosplenomegaly**
1. thrombocytopenia
2. increased **infection** risk
7. Hypothyroid and hypoparathyroid
27
Aplastic anemia is caused by
1. **Bone marrow failure** characterized by destruction of rapidly growing cells
2. Marrow damage from:
1. Drugs (all kinds)
2. Radiation
3. Chemotherapy
4. Infectious diseases
3. CBC values extreemly low
28
Aplastic anemia
perioperative risks and concerns
* Often on immunosuppression
* may need "**stress dose"** steroids
* **Reverse isolation**
* Prophylactic **antibiotics** d/t neutropenia
* **Hemorrhage** (GI and intercranial)
* **LV dysfunction** due to high output state
* **Difficulty in cross-matching**
* (have had multiple transfusions)
* Co-existing **congenital** abnormaliities
* (Fanconi anemia - peds- cleft palate and cardiac defects)
29
Co-existing congenital abnormalities with aplastic anemia
Fanconi anemia in peds
* Cleft lip/palate
* Cardiac defects
30
aplastic anemia
## Footnote
**Induction**
* Consider preop transfusion
* Airway Hemorrhage possible with DVL
* Avoid nasal intubation
* Consider Regional if coags allow
* Will have labile hemodynamic response to induction
31
aplastic anemia
Maintenance
* PEEP will allow for lower FiO2
* Avoid nitrous (immunosupression)
* Maintain normothermia
32
aplastic anemia
Emergence
* Extubation and post-op perioid are the periods with greatest oxygen demands
* Monitor coagulation status
33
Methemoglobinemia
What is it?
What casues it?
1. Formed when iron in Hgb is oxidized from the ferro**_us_** to the ferr**_ic_** state (2+ to 3+)
2. **LEFT** shift = little oxygen delivery to the tissues
3. Normal blood level = **1%**
4. At **30-50%** methemoglobinemia there will be signs of **oxygen deprivation**→**BROWN** blood
5. Over **50%** can lead to coma and death
**Causes:**
* **Nitrate** poisoning (SNP)
* Toxic drug reactions
* such as from **prilocaine** (throat spray)
34
Anesthesia considerations for metHgb
1. Makes the pulse ox **inaccurate**
* MetHgb absorbs red and infrared light **equally**
* at SaO2 **over** **85%** → true value is **underestimated**
* at SaO2 **under 85%→** true value is **overestimated**
(just think the OVER/UNDER RULE!!!)
1. Toxic Methemoglobinemia requires emergent treatment
1. Oxygen
2. _Methylene Blue 1% solution_: **1-2 mg/kg** over **3-5** minutes
* Mary repeat after 30 minutes
35
* Clinical Signs of **acute** blood loss
**20% acute blood loss:**
* Tachycardia
* Orthostatic hypotension
* CVP changes
**40% acute blood loss**
* Tachycardia
* (may have EKG chnages d/t change in O2 carrying capacity)
* hypotension
* tachypnea
* oliguria
* acidosis
* restlessness
* diaphoresis
36
Acute blood loss
Treatment
1. **Restore intervascualr volume**
* (crystalloids, colloids, blood products)
2. **Monitor Labs**
1. **Coagulation**
* CBC (Hgb/HCT, platelets), PT, PTT, INR, fibrinogen
2. **Calcium** and **potassium**
3. **ABGs** (persistant metabolic acidosis reflects hypovolemia and inadequate oxygen delivery to the tissues)
3. **Hemodynamic monitoring**
1. CVP, A-line, +/- PA
2. do they have adequate urine output? Hematuria?
37
Blood loss
Induction, maintinence and Post op
1. **Induction:** Ketamine/Etomidate
2. **Maintinence**
* May too unstable for ANY Inhaled anesthetics
* trauma cocktail = scopolamine, benzo, opioid mix
* Keep warm
* use pressors sparingly→not treating the problem!
* watch surgical field for non-clotting blood
3. **Post-operative**
* May need post op ventilation
* Risk for Pulmonary edema and ARDS
38
Definition massive transfusion
what are consiquences of massive transfusion?
**_Definition_**
* More than **10 units PRBCs** in **24 hour period**
* Replacement of at least **one** blood volume in **24 hours**
* **50%** blood volume replacement in **6 hours**
**_Consiquences_**
* Hypothermia
* Volume overload
* Dilutional coagulopathy
* Decreased 2,3-dpg
* Hyperkalemia
* Citrate toxicity (hypocalcemia)→hypotension
* Tissue hypoperfusion and lactic acidosis
39
Polycythemia
What is it?
Problem?
**Increased Hct and high RBC mass → caused by:**
* dehydration
* Excess RBC production (polycythemia vera)
* Chronic hypoxia
**Increased blood viscosity poses risk for:**
* Thrombosis leading to CAD, pulm HTN, CNS disorders
* Hct **\> 55%** is problematic
40
Hemophilia A
Anesthesia considerations
1. **Factor VIII (8 deficiency)**
2. **Increased PTT NORMAL PT**
* **Severe→ (**VIII \< **1%)** **childhood** diagnosis **→** spontaneous hemorrhages; **joints**, **muscles**, **organs**
* **Moderate****→ (**VIII**1-5%)**high bleeding risk in surgery**→** Have less joint bleeding problems
* **Mild→** (VIII = **6-30%**)**→****adult**diagnosis**→**bleeding risk in**MAJOR** surgery
3. **Anesthesia considerations:**
* **Pre-op factor VIII** →start at 100% then mintain at \>50%
* IV: **50-60** U/kg loading *_then_* **25-30** U/kg **q8-12** hours
* E1/2 = 12 hours
* May need for **two weeks** post op.
* DDAVP is also effective at correcting for surg
41
Hemophilia B- Severe, moderate, mild
**Congenital Factor IX deficiency**
**Increased PTT normal PT**
* **_Severe_** (factor **IX** \< **1%)→** severe bleeding
* **_Moderate_**(factor **IX = 1-5%)**
* **_Mild_** (factor IX = **5-40%)**
**Anesthesia Considerations**
* GIVE factor IX **prior to surgery**!!!
* 7000 Units (70kg) = 100 U/kg
* Half life is **18-24** hours, so 50% of original dose needs to be given every **12-24 hours** to keep levels about 50%.
* Treatment can result in **increased thromboembolic** events
42
von Wilibrand disease
Anesthesia considerations
Von Wilibrand Disease
* Dysfunctional platelets (NORMAL plt count)
* prolonged Bleeding time (\>10 minutes)
* Increased PTT
* **Bleed from mucus membranes**
* ****epistaxis, bruising, menorrhagia, gingival and GI bleeding
**_Anesthesia Considerations_**
* **Avoid messing with the nose** (intubation/trumpets)
* **Desmopressin** (DDAVP) IV or intranasal
* IV: 0.3mcg/kg in 30-50ml NS over 10-20 minutes
* Intrnasal = 300mcg divided between each nostril
* (can produce tachycardia and hypotension)
* **Cryo** for severe bleeding or surgical prophylaxis
43
Compare Labs and Treatment
Hemophelia A, Hemophelia B and von Wilibrand disease
44
**Platelet Dysfunction**
Causes and Treatment
Drugs
1. **Asprin/NSAIDS**
* Inhibits aggregation for life of the platelet
* **bleeding time** = **2-3x** longer within 3 hours of ingestion
* **72 hours** = returns to normal
* Aggregation inhibited up to **10 days**
2. **Antibiotics**
* Interferes with platelet **adhesion** and **activation**
* Biggest impact on **critically ill**
3. **Volume expanders**
* **dextran** = platelet inhibition
* **hespan** = dilutional thrombocytopenis
**Other Factors**
1. **Hypothermia \< 35˚C**
2. **Acidosis (pH \< 7.3)**
3. **Uremea and liver disease**
**Treatment**
1. **vWF in Cryo**
2. **Desmopressin DDVAP**
3. **Platelet transfusion**
45
Thrombocytopenia
what is it?
signs and symptoms
goals and treatment
* **Low platelet count**
* approximately **1/3** of platelets sequestered in spleen
* Signs:
* Petechial rash
* nose bleeds
* GI bleeds
* bruising
* Need **\>50,000** for major surg
* A **six pack** of platelets should increase platelets by about **50,000**
46
Most common intra-op coagulopathy
* Dilutional thrombocytopenia or coagulopathy
* occurs when blood loss replaced with **crystalloid**, **colloid** or **PRBCs**
* dilution of platelets and clotting factors
* occurs with massive transfusion (more than 10 units)
* Surgical hemorrhage also causes **fibrinogen** release from hepatic stores
47
Acquired defects in platelet production
* Radiation
* Chemo
* Toxic chemicals
* Thiazides,
* ETOH,
* estrogen
* Cancer
* Viral hepatitis
* B12/folate deficiency
48
DIC
What is it?
what is it associated with?
Clinical symptoms?
Labs
Treatmetn
DIC = diseminated intravascular coagulation
1. **Classified as a Consumptive coagulopathy**
* Bleeding, microemboli, consumption of platelet and clotting factors, fibrin deposits and impaired fibrin degredation
2. **Associated with:**
* sepsis, trauma, cancer, immune disorders
* OB complications, vascular disorders
3. Clinical symptoms d/t **thrombosis** and **bleeding**:
* microemboli accumulation in the pulmonary system
* organ damage
4. **No single lab test diagnostic**
* Rapid decrease in PLT to \<50,000
* Prolonged PT/PTT
* Presence of split fibrin degridation products
* Normal Fibrinogen levels
* Low plasma Antithrombin III
5. **Treamtment = manage casue and coagualtion process**
* PLT, FFP, Fibrinogen, Antithrombin III
* Heparin (Blocks thrombin and faciltates hemostasis)
* Hemodynamic and respiratory support
49
Tests of Coagulation
Lab Values
Clotting factors
50
Vitamin K deficiency
1. Vitamin K is needed for formation of factors
* II, VII, IX, X
2. **Causes**:
* Malnutrition/malabsorbtion
* Antibiotic induced elimination of intestinal flora
* Liver Disease/obstrucyive jaundice
3. **Lab profile:**
* Prolonged PT, NORMAL PTT
4. **Treatment:**
* Vitamin K (takes 6-24 hours for effect)
* FFP for acute bleeding
51
Hypercoagulability Disorder
Causes
Anesthesia considerations
**_Causes of Hypercoaguability disorders_**
* Malignancies, Pregnancies, Oral contraceptives
* Lupus, Nephrotic syndrome
**_Anesthesia considerations_**
1. Prevent thrombus, PE, DVT, blood clots
* Early ambulation
* SubQ heparin
* Compression devices
* ASA
* IVC filter
* Regional anesthesia is beneficial, but **contraindicated if pt on LMWH**
52
What is long-term anticoagulation therapy used for
**_Long term anticoagulation used for:_**
* **A-fib,** Venous thrombosis and heart valves
* Hereditary hypercoagulable states
* Cancer
**(Threapy poses a problem at the time of surgery → MUST evaluate the risk of thrombosis with the risk of bleeding)**
53
Antiplatelet therapy is indicated periop for what conditions? Which meds are commonly used?
**Antiplatelet therapy indicated for:**
* Pts at high risk for **CVA**, **MI**, vascular **thrombosis** complications
**Medication used**
* **ASA**, **PDE** inhibitors, **ADP** receptor antagonists
54
Warfarin
Anesthesia considerations
* **Mechanism**
* Competes with **vitamin K** →inhibits formation of vitamin K dependent clotting factors
* factor **II, VII, IX,** and **X**
* **Lab tests:** PT/INR
* **Reversal:** Vitamin K, FFP, 4 factor PCCs
* **Holding Warfarin prior to surgery:**
* At least 5 days
* check INR **_ONE_** day preop,
* if \> 1.8→ give 1 mg vitamin K subQ
* **If they are high risk and cannot go without anticoagualtion**
* Start heparin **3 days** after stopping warfarin
* Stop heparin **6 hours** prior to surg
* surgery can be safely performed if INR \<1.5
* (regional??? I wouldn't)
55
Heparin
Anesthesia connsiderations
**Mechanism**
* **INDIRECTLY** inhibits **thrombin** and **Xa** by binding to **antithrombin III**
**Lab tests:** PTT or ACT
**Reversal:** Protamine
**Complication**: HIT (thromboembolic complication)
56
What is P50
* the **partial pressure** at which **50%** of hemoglobin is saturated
* Usually around **26-28%**
* A **right** **shift** needs a higher partial pressure to sarurate **50%** (left shift = lower PP)
57
Relative partial pressures and oxygen saturation
At **40** mmHg **70%** of hemoglobin will be saturated
At **60** mmHg **90%** of hemoglobin will be saturated
58
Explain the steep part of the oxyhemoglobin disassociation curve
* there is a **rapid unloading** of O2 in response to a small change in the partial pressure of O2
59
Treatment for acute blood loss
1. **Restore intervascualr volume first!!!**
* Colloid
* crystalloid
* Blood products (O2 carrying capacity)
2. **Monitor coagulation**
* (blood loss **decreases** **clotting** **factors**)
* PT, PTT, INR, CBC, PLT
* If you see oozing in the surgical field **CHECK FIBRINOGEN!!!**
3. Monitor serum **calcium** and **potassium** levels
1. **citrate** binds to calcium
2. **blood** **products** have high potassium and will have a higher contenct as the cells degrade
3. **Hypotension? may need some calcium!**
4. ABGs
* **_persistent metabolic acidosis_** reflects reflects **hypovolemia** and **decreased** **oxygen** **delivery** to the tissues
