1. Onchematologic emergencies
Dr. Demeter Judit
Semmelweis Egyetem ÁOK., I.sz. Belgyógyászati Klinika

2. Onkohematologic emergencies
Hemodynamic - vena cava superior syndrom NHL - pericardial tamponade lymphomas - hyperviscosity syndrome MM, Wald. - thrombosis myeloprolif.
Hematologic - bleeding qualitative-quantitive pathologies of platelets ITP lack of coagulation factors DIC (M3)
Nervous system - spinal cord compression NHL, MM immediate MR! - koponyaűri nyomásfokozódás NHL
Metabolic - tumorlysis syndrome hyperuricaemia, hyperkalaemia - hypercalcaemia MM, NHL - hypokalaemia AML - hypoglykaemia insulinoma
Other - TTP/HUS

3. Incidence:
number of patients with hematologic and oncologic malignancies is increasing
The number of patients presenting with hemato-oncologic emergencies is expected to be increasing

4. Prospects:
patients cancer no longer should be looked upon as incurable and terminal even not even in the emergency departments
Patients are to some degree amenable to therapy or intervention
Following the succcesful treatment of an emergency condition, these patients may lead relatively normal lives.

5. mechanical emergencies
1.neutropenic fever.
the most common !
mechanical emergencies
airway obstruction,
superior vena cava syndrome
cardiac tamponade
spinal cord compression.
metabolic emergencies.
hyperviscosity syndrome
hypercalcemia
syndrome of inappropriate antidiuretic hormone secretion (SIADH)
acute tumor lysis syndrome.
Often missed! superior sulcus lung tumor (Pancoast syndrome).

6. Infectious Emergencies Neutropenic Fever
appropriate recognition and management may significantly lessen morbidity and mortality!
Neutropenia
absolute granulocyte count is < 500 cells/µL
or < 1000 cells/µL with an anticipated decrease to < 500 cells/µL.
nadir mostly between 2-4 weeks after chemotherapy
Fever if if temperature exceeds >38.3° (101° F) or
if the temperature = 38.0° C (100.4° F) for > 1 hour.

7. lack of circulating white blood cells.
few of the classic signs and symptoms of bacterial infections
e.g. significant pneumonia without cough or infiltrates on plain film. urinary tract infection
without WBC deposition in the urinary tract , lack of dysuria and frequency.
meningitis may present without clinical evidence of meningismus or cerebral spinal fluid pleocytosis.
Febrile neutropenia: cultures of blood and urine
chest x-ray performed (chest CT even better!)
if indwelling central line : at least one set of blood culture through it!

8. Immediate empiric antibiotic therapy!
( because progression of infection in neutropenic
patients may be very rapid)
Initial antibiotic therapy should be tailored to the suspected offending pathogens.
In the not too distant past, neutropenic patients were covered with two antibiotics, typically a third-generation cephalosporin in combination with an aminoglycoside. Traditionally, G-negative bacilli ( Pseudomonas, E coli, and Klebsiella): most common offending pathogens.
Nowadays: increase in the rate of infections caused by gram-positive bacteria, (some of them methicillin-resistant) .
Staphylococcus aureus
coagulase-negative staphylococci most common causes, particularly in patients with an indwelling catheter
Recommended: single agent antimicrobial therapy (monotherapy).
third or fourth-generation cephalosporin (ceftazidime or cefipime)
or a carbapenem (imipenem-cilastatin or meropenem)

9. clinically-suspected serious catheter-related infections
. Include vancomycin in the treatment if:
clinically-suspected serious catheter-related infections
known colonization with methicillin-resistant Staphylococcus aureus
positive results of blood culture for gram-positive bacteria before final identification and susceptibility are known
hypotension or other clinical evidence of cardiovascular impairment
Growth factor treatment: filgrastim (Neupogen).
stimulates WBC production
reduces the duration of neutropenia and fever,
reduces the requirement of parenteral antibiotics
reduces the duration of hospitalization.
safe even in acute leukemia
Granulocyte transfusion not recommended!

10. Management of neutropenic fever
1. initial antibiotic of choice:
third or fourth generation cephalosporin or a carbapenem.
(single agent therapy)
2. Cultures of blood and urine !
3. Consider chest CT if pulmonary symptoms present (active pulmonary infections may be present despite normal chest x-rays)
4. Vancomycin if indwelling intravenous catheter infection suspected
(in addition to gram-negative coverage).
5. rapid institution of empiric antibiotic therapy reduces morbidity and mortality.
6. reverse isolation room.   

11. Mechanical Emergencies:
Spinal Cord Compression
any patient who presents with back pain may have spinal cord compression due to malignancy!

12. She developed paralysis and incapacitating pain.
disseminated metastatic breast cancer to bone (after both chemotherapy and radiation therapy).
She developed paralysis and incapacitating pain.
MRI image: extensive bone tumor with collapse of the T10 and T11 vertebrae resulting in spinal cord compression.  

13. Epidural spinal cord compression
devastating complication of many malignancies
breast
lung
prostate cancer
AML (chloroma)
muItiple myeloma
Frequency ca. 5%
Importance of early detection in remaining ambulatory!

14. Epidural spinal cord compression
Might be the first clinical manifestation of malignancy.
Pts with known diagnosis of cancer (breast, lung, prostate, renal) + back pain
potentially lethal back pain entities
cancer
cauda equina syndrome
abdominal aortic aneurysm,
back pain and a history of malignancy should be assumed to be metastasis to the spine or epidural spinal cord compression until proven otherwise

15. Epidural spinal cord compression
Presenting symptoms
numbness
tingling
sensory loss
bowel or bladder incontinence
abnormalities of proprioception e.g.loss of vibratory sense
back pain worsened by particular maneuvers, such as (coughing or lying in a supine position
pain that is worse at night.
New-onset radiculopathy from compression of a spinal root may also be the first manifestation of tumor (DDG: A herniated disc)

16. Epidural spinal cord compression
The physical examination may show evidence of spinal cord compression with paralysis or may be completely normal and unrevealing.
A detailed motor, sensory, and deep tendon reflex examination should be performed in all patients with suspected spinal cord compression, as well as observation of gait and evaluation of sphincter tone

17. Epidural spinal cord compression
think about the diagnosis in patients with back pain!
Dg-ic workup: Magnetic resonance imaging
epidural spinal cord compression can be subtle, and detection requires a high index of suspicion!
Treatment:
high dose corticosteroids - decompressive laminectomy - radiation

18. Epidural spinal cord metastasis and/or compression.
Pain may be the only finding !
Suspicious: Pain worsened by cough or the supine position
2. Physical examination:
midline bony tenderness (often absent),
ataxic gait
weakness
autonomic dysfunction (bowel or bladder incontinence).
3. Corticosteroids –iv. immediately!
4. Think about the diagnosis!

19. Superior Vena Cava Syndrome
becomes an emergency with the development of
cerebral edema (life-threatening cerebral herniation) or
laryngeal edema (leading to airway compromise)
Causes: ( tuberculosis, aortic aneurysm, and fibrosing mediastinitis)
Nowadays: lung carcinoma
lymphoma
catheter-related superior vena cava thrombosis.

20.  Thickening of the prevertebral soft tissue shadow indicates laryngeal edema

21. Superior Vena Cava Syndrome
Clinical manifestations:
protean
depend on the degree of vena cava obstruction.
Fom relatively asymptomatic with only mild facial fullness when bending forward or may have florid symptoms of facial swelling, headache, and airway compromise.

22. A clue to the diagnosis is the presence of asymmetric neck, chest, or upper arm venous distension.
One diagnostic tool that has been employed by some is to compare the patient’s appearance to that of a picture of the patient, often a driver’s license
Subtle and sometimes marked changes in the physical appearance of the patient’s face can be identified.

23. The key to understanding the variability of the clinical presentation is the anatomy of the azygous vein.
The azygous vein is a large vessel that enters the proximal superior vena cava and drains blood from the thorax.
Obstruction above the level of the azygous entry point may lead to relatively few symptoms due to the ability of the azygous to decompress the upper extremities, head, and neck.
If a compressive lesion or thrombus obstructs the SVC below the entry point there is no mechanism for upper torso, head, and neck decompression, and patients may present with marked venous collateral formation and facial swelling on examination .

24. dezsine

25. Patient’s driver’s license before cancer diagnosis-
Picture 1 year later  

28. Superior vena cava syndrome
Traditional teaching : most patients present with a sensation of facial fullness, facial swelling, cough, variable arm swelling, and dilated neck and upper chest wall veins, with these it would not be a difficult diagnosis to make.
However, this oncologic entity may present with few if any clinical findings.
Further frequent symptom:
sensation of fullness when bending forward
or a vague, chronic cough.
However, if venous decompression is able to occur, there will be no prominent veins or facial swelling the diagnosis may not even be considered.

29. Depiction of the azygous vein (denoted by asterisk)
Depiction of the azygous vein (denoted by asterisk).  Diagram on the left indicates point at which the azygous enters the SVC and its relationship to intercostal vessels. 

30. Treatment aim:
alleviating congestive symptoms while simultaneously attempting to make a definitive diagnosis.
In cases where suspected or confirmed lung cancer or lymphoma is the cause, institution of radiation therapy may help lessen venous congestion and reduce upper torso, head, and neck venous pressure.
Previously, superior vena cava syndrome was considered an emergency. Today, emergent radiation therapy should be reserved for patients with life-threatening laryngeal or cerebral edema.

31. Patients with a confirmed or suspected diagnosis of SVC syndrome
based on clinical grounds should undergo CT scanning
to define the degree of SVC obstruction and
to evaluate for the possibility of thrombotic SVC occlusion (10).
If no known tissue diagnosis of cancer has been done,
a biopsy is typically performed as an outpatient or inpatient.
Adjunctive treatment modalities such as steroids and diuretic therapy
may be used, particularly if head and neck edema is a prominent feature.

32. Superior vena cava syndrome caused by lung carcinoma
Superior vena cava syndrome caused by lung carcinoma.  Notice the ruddy appearance of the patient's face caused by elevation of the arm - Pemberton's sign. 

33. Superior vena cava syndrome
1. A complaint of facial swelling should be enough to make the emergency physician consider the diagnosis of SVC syndrome. Partial SVC occlusion or compression above the azygous vein may not lead to any physical exam findings.
2. Hoarseness may be a subtle clue when laryngeal edema has developed.
3. Stoke’s sign - Face and neck swelling seen in SVC syndrome
4. Relatively rare but pathognomonic of SVC syndrome is supine facial cyanosis: development of facial cyanosis when the patient is placed in the supine position.
5. Subtle presentations are common and include fatigue (due to poor venous return), dyspnea, chest pain, headache, face and neck swelling, and facial flushing.
6. Incidence of thrombotic SVC syndrome is on the rise.
7. Symptoms tend to be worse upon awakening secondary to venous pooling.

34. Clinical presentation of a patient with superior vena cava syndrome.

36. Injury/Microorganisms Microcirculatory disturbances
DIC
Injury/Microorganisms
Activation of -PMN -Macrophage -Endothelium
Cytokines
Systemic activation of coagulation
fibrin formation
Toxins
Microclot formation
Consumption of coagulation factors and inhibitors
Secondary fibrinolysis
Microcirculatory disturbances
Bleeding
Organfailure

37. Thrombotic microangiopathies
A THROMBOTIC THROMBOCYTOPENIc PURPURA (TTP) ÉS A HAEMOLYTIC URAEMIC SYNDROM (HUS)
Have microvascular platelet aggregation in common
But.: TTP can be regarded as a systemic dsorder,
HUS: is localized to the kidneys.
TTP és HUS have very many similarities .
Similar starting events :… TTP/HUS complex

38. TTP and HUS consumptive thrombocytopenia
microangiopathic haemolytic anaemia
ischaemic symptoms
TTP
HUS
TTP
HUS

39. Diagnostics, morphology
Megakaryocytic thrombocytopenia
Fragmentocytes

40. Thrombotic thrombocytopenic purpura ( Moschcowitz syndrome, 1924)
Incidence: 30 patients have to be treated in Hungary yearly
Mortality of untreated cases : %.
A diagnostic criteris: (first 2 criteria are sufficient)
Severe consumptive thrombocytopenia, - plenty of megakaryocytes
Fragmentocytic haemolytic anaemia, direct Coombs neg
Fluctuating neurologic symptoms
Kidney involvement – renal failure
Fever

41. TTP – clinical pentade Moschcowitz: 1924 consumptiive thrombocytopenia
microangiopathic hemolytic anaemia
fluctuating neurológical symptoms
Kidney involvement – renal failure
fever
triad: %, pentade: 40 %

42. TTP -frequency incidence: 1-7 / 1 million inhabitants / year
Typical age: decade
female : male ratio: 3 : 2
Mortality before1960: > 90 %
Mortality after : %

43. TTP – clinical forms Acute (single episode) TTP: no relapse
Intermittent TTP: relapse occurring irregularly
Chronic cyclic TTP: relapse at regular intervals

44. Differentialdiagnosis:
DIC
HELLP sy
ITP
Evans sy
Antiphospholipid sy
Liver diseases
Paroxysmal nocturnal haemoglobinuria (PNH)
Other causes of mechanical hemolysis (arteficial valve, etc.)

45. Haemolytic uremic syndrome
A diagnostic criteria: all the three have to be present)
Thrombocytopenia, number megakaryocytes in the BM normal or increased.
Fragmentocytic haemolytic anaemia, a direkt Coombs test negatíve (kivéve: neuraminidase infekciókhoz társuló secunder formák).
Variable degree of kidney involvement, kidney failure
Clinical forms:
Diarrhoea-asszociated or típical HUS: benign form, mortality less than 10 % .
Sporadic or atypical HUS, high mortality, (ca..70 %.) no accurate data on incidence.

46. Treatment of TTP and HUS
aim: curative.
Only in hospitals with intensive care units
Treatment: Plasmaexchange, daily,, substitution with fresh frozen plazma or cryo-supernatant : thus % of patients might be cured.
Alternativ therapy: Fresh frozen plasma or infusion of fresh frozen plasma: signifivcatnlyx less effective than plasma exchange,
Futher drug therapies Corticosteroids - Thrombocyta aggregácion inhibitors? - Vincristine - Immunosuppressive drugs - potentially high dose iv. Ig

47. Supportív therapy:
RBC transfusion,
Platelet transfusion is usually contraindicated!
Treatment of infections
Dialysis
Intensive care unit (ritkán gépi lélegeztetés, parenterális táplálás)
Treatment of precipitating cause in the case of secondary forms

48. Hematological indications of apheresis I.
Hyperleukocytosis
Leukostasis
High peripheral cell counts + chemotherapy causing acute cytolysis
High peripheral cell counts + organomegaly causing severe compression symptoms
Extremely hig cell numbers a. myeloproliferatív sy: WBC > 300 G/l b. lymphoproliferatív sy: WBC > 500 G/l
Thrombocytosis
With complications (threatening ot manifest thrombosis and/or bleeding
plt > 1000 G/l + pregnancy
plt > 1000 G/l + before a planned operation or coronarography ( maximally 2 aphereses végezhető)
4. thr > 1000 G/l + thrombophilia proven by a laboratory test
TTP
Apheresis shlould be stopped in the case of hematological remission or (brain)death

49. HUS Gasser: 1955 consumptive thrombocytopenia
microangiopathic haemolytic anaemia
Acute renal failure

50. Typical HUS (diarrhoea associated)
verotoxin / shigatoxin
Characteristic prodromal phase
endemic
Young age (< 5 years)
low mortality
rare relapse following kideny transplantation

51. Sporadic (atypical) HUS (not diarrhoea associated)
not verotoxin / shigatoxin associated
No characteristic prodromal phase
not endemic
elder age (> 5 years)
high mortality
frequent relapse following kidney transplantation

52. Etiology idiopathic familiar secundary
infections: verotoxin / shigatoxin
neuraminidase
HIV
other
Pregnancy and postpartum period
Autoimmune disorders
tumors, chemoterápy
drug: kinin, ticlopidin, (clopidogrel), cyclosporin,
tacrolimus, mitomycin, contraceptives, stb
Allogeneic stem cell transplantation

53. Feltételezett pathomechanizmus
prostacyclin termelés zavarai
csökkent fibrinolysis
exogen toxinok, enzimek
thr aggregáló faktorok
pap37
calpain
endothel sejt apoptosis
autoimmun mechanizmus
autoantitest: endothel, CD36
immunkomplex
vWF eltérései

54. Jelenlegi hypothesis (a distintegrin and metalloprotease with eight
TTP-s microthrombosisok: vWF + thr
kóros vWF multimer eloszlás (ULvW)
nyíróerő: vWF - direkt thr aggregáció
áramlási cytometria: thr-hoz kötött vWF
FFP vagy cryofelülúszó transzfúziója
klinikai remissio
vWF multimer eloszlás normalizálódása
vWF cleaving protease: ADAMTS13
(a distintegrin and metalloprotease with eight
thrombospondin-1-like domains) 9q34 kromoszóma
ADAMTS13 enzimaktivitás csökkenése/hiánya
autoantitest - ADAMTS13 enzim inhibitor
congenitális enzimhiány

55. VWF Cleaving Protease (ADAMTS13)
Metalloprotease
Thrombospondin 1
CUB S M P
Cys D
Spacer 1 2 3 4 5 6 7 8
Disintegrin
A Disintegrin-like And Metalloprotease
with ThromboSpondin-1 repeats

56. Laboratory abnormalities.
microangiopathic haemolytic anaemia
fragmentocytosis, nucleated RBCs
basophil punctation
reticulocytosis
negatív direct Coombs teszt
Slightly elevated indirekt se-bi
Reduced or non-detectable serum haptoglobin
haemoglobinuria, haemosiderinuria
thrombocytopenia
thr << 50 G/l (TTP)
thr < G/l (HUS)

57. Laboratory abnormalities - 2
Significantly elvated serum-LDH (2-20x)
se-kreatinin
variable (TTP)
increased (HUS)
Hemostatic abnormalities
normál prothrombin, PTI, fibrinogén
Urine
haematuria, proteinuria, cylinders
CRP: normal or slightly increased
Liver enzymes: normal or slightly increased

58. Differentialdiagnosis
TTP or HUS
DIC
(pre)eclampsia / HELLP sy
systemic vasculitides
thrombocytopenia or haemolysis of other causes

59. Treatment results – empiric plasma therapy
Idiopathic TTP/HUS
complete haematological remission: %
Relapse within 10 years: %
Secundary TTP/HUS
Variable, depends on underlying cause

60. Evidence based plasmaexchange since the early 1990-s
: plazmaexchange / plasma transfusion
: prospektíve randomized controlled study
plasmaexhange or plazma transfusion?
- Rock: N Engl J Med 1991;325:393
- Henon: Transfus Sci 1992; 13:63
PLASMAEXCHANGE!

62. Hematological indications of apheresis – II.
HUS
1. All adult cases 2. Childhood atypical HUS 3. Childhood therapy resistant HUS
Apheresis should be stopped at the time of haematoligical remission independent of the renal status
HELLP sy
thrombocytopenia, haemolysis, SGOT >70 U/l, LDH>600 U/l, if:
Symptoms persist hours follwing termiantion of pregnancy resistant to conservative treatment
With postpartum eclampsia
The usual gynecologic causes of DIC should be excluded before start of apheresis

63. Hematologial indication of apheresis – III.
Gammopathies
hyperproteinaemia: total protein > 100 g/
2. hyperviscosity sy: blood viscosity is more than 15 % above what is normal for the given Ht
Acute renal failure caused by paraprotein
4. polyneuropathy
Cryoglobulinaemia
kryokrit > 1 %, if 1. Raynaud sy and/or necrotising cutan vasculitis 2. cryoglobulinaemic vasculitis
Cold type AIHA
haemolytic crisis
Masszíve intravasal haemolysis
Impending renal failure

64. Hypercalcaemia malignus betegségekben
Általános jellemzők

65. Hypercalcaemia non-Hodgkin lymphomákban
Gyakorisága: összes NHL 4%-a (9/219) (kifejezett mal. NHL: 30%)
Mechanizmusa: calcitriol-mediált (19 esetben egyidejű hypercalcaemia és hypercalcitriolaemia)
a növekedett calcitriol szint valószínűleg extrarenalis eredetű
nincs jellemző csontváltozás

66. In patients taking salicilates, ticlopidin or clopidogrel, no operation should be performed ( no stomatological procedure!)

67. A calcitriol-mediált hypercalcaemia kezelése
corticosteroid önmagában is hatásos
további kezelési lehetőségek
Csontokból calciummobilizáció gátlása (osteoclastok gátlása: calcitonin, biszfoszfonátok)
bélből calciumfelszívódás csökkentése: Ca szegény étrend
renalis calciumürítés csökkentése hypovolaemia korrekció FONTOS TOVÁBBÁ: - UV sugárzás kerülése - D vitamin bevitel kerülése

71. Ferezissel eltávolított leukémiás massza ( 10 l feletti)
CML blasztos fázisban diagnosztizált
34 éves beteg esetében