Acute Sickle Cell Crisis

M. Domenica CappelliniFondazione “Ca Granda” Policlinico

Università di Milano

Muravera8-12 june 2015

EFIM Summer School 2015

SCD as emerging problem of public health in non endemic areas

Weatherall DJ et al. Bulletin WHO 79: 704, 2001; Modell B et al Bulletin WHO 86: 480, 2008

Sickle cell mutation Falciparum malaria

Eaton JW, et al., eds. Sickle cell disease: basic principles andclinical practice. New York: Raven Press Ltd. 1994.

Selection of the sickle cell traitHbS mutation protects against

Plasmodium falciparum infections

HbS = sickle cell haemoglobin.

SCD is now a global diseaseSCD is now a global disease

Worldwide Status of Hemoglobin disorders

• 270 million carriers of Hb disorders:80000 of Thalassaemia, most of Sickle Cell Disease.

• 300000 affected births per year total.• 60-70000 births of Thalassaemics: most

of these die in early life, often with no diagnosis and no or inadequate treatment.

• About 200000 new cases of SCD per year.

Agastiniotis M. WHO Report 2004

Hemoglobinopathies are Emerging Problem of Public Health based on YLD and DALYs (1999-2010; 2010-2055)

YLDs: years lived with disability for hemoglobinopathies (β-thal and SCD): 10.197 vs 21.342 cardiovascular disorders

DALYs: disability adjusted life years for hemoglobinopathies (β-thal and SCD): 15.640 vs 75.000 diabetes Murray CJ et al Lancet 380: 2197, 2012; Kassebaum NJ Blood 123: 615, 2014

50 million heterozygous HbSindividuals in the world

• Africa– 10–40% HbS mutation carriers in the population – 200,000–300,000 SCD newborns/year

• USA– 1 SCD newborn/600 births in Afro-American population – 60,000–70,000 SCD patients

• France– 405 SCD newborns in 2007 – 10,000 SCD patients

de Montalembert M. Br Med J. 2008;337:a1397.

Case 1• Female, 34 yrs, Nurse, from Sicily leaving in Milan • Admitted at ER on 19/4/2011• Since 3 days she complained left back pain

unresponsive to pain killer. • Since 2 days fever, cough, worsening dyspnea.• Past History: diagnosis of Sickle/thal in childood. She

had pregnacy at 32yrs (cesarean delivery). Bladder stones

• She uses NSAIDs whenever she has pain, She was occasionally transfused in the past, she was admitted to hospital in several occasions because of back pain

Physical Examination

• She was well oriented, suffering, with shortness of breath (dyspnea)

• pale, without cyanosis• BP 140/90, HR110 r, RR 28-30/min,

O2sat. 94% , T 36.8°C• Heart sounds normal but frequent• Reduced left chest expansion• Vescicular breath sounds reduced at lower

left fields

Lab tests

• WBC 11.9;GR 3.87, Hb 8.7g/dl , Ht 27%, MCV 70fl, MCH 22.5, MCHC 32.1, Plt 359

• Crea 0.6, Na 139, K 3.6, Alt 15, Bil. tot. 3.0 PT 83% (inr 1.12), PTT 30”, D Dimer 0.44 ( v.n 0.29 microg/ml)

• ECG: tachycardia • Rx thorax

ER therapy

• Oxygen delivery• NSAIDs e.v.• Hydration e.v.• Antibiotics (Macrolide e.v.)

Admission in emergency medicine ward

• 19/4 • Pain and polipnea, fever,

repeated blood cultures• 1 unit of RBC • NSAIDs not efficacious• Transient benefit by

oppioid • Early antigens: negative

• 20/4• Clinical status was

worsening• O2 , 1 unit RBC• Increase of antibiotic

spectrum analgesia, (cefalosporine III gen)

• Increase analgesia • esami, rx thorax, CT

thorax • Admitted to intensive

care room

Admission to Intensive Care• Sedation, intubation, analgesia• Blood transfusion/ antibiotics(+ Bactrim

ev)• Cultures: negative• Fever: 37.4°C• Improvment of xray thorax• extubated 24/4• Back to emergency medicine room

From 26/4 recurrence of pain and fever PCR decreasing, CVC removed (culture neg).

Reintroduction of FANS and oppioid.Respiratory status stable

Treatment: IMIPENEM + TEICOPLANINANo active hemolysis

Pregressive improvment Discharged on 6/5

Case 2

• Female 45 yrs, well educated, english teacher• In childood diagnosis of SCD• Colecistectomy in 1984, twin pregnancy in1986

cesarean delivery• Anemia (9-10g/dl), LDH >1000, Bil. Ind. > 4mg/dl• 3-4 sickling crises/year well controlled with

analgesics and hydration

Caso clinico 2• From 1995 on blood transfusions

(approximately every 3 months to keep HbS< 40%)

• End of june 2006, good general conditions, she transfused and she went on holidays

• 20.8.06: 2 days cough, moderate thorax pain• Fever38.7°• A GP of the area was consulted and he

prescribed oral antibiotics

Caso clinico 2• 21.8.06: fever 39.4. The GP visited the

patient again and found a worsed situation: the pt was well oriented however suffering; poli/dysponoic

• They call the ambulance for transfer in ER• The ambulance arrived after 1 hour• The patient arrived in ER with Acute Chest

syndrome• At 6pm she died

Waiting at Sickle Cell Clinic, KATHGhana

Courtesy of Dr H. Wajcman.

Haemoglobin S [β6 (A3)Glu→Val]

H. Wajcman

De-oxygenate SLOW

Oxygenate FAST

Therefore

• The pathophysiology of SCD is explained – either by a decrease in the time needed for

polymerization• red cell dehydration • HbF%

– or by an increase in the time during which the red cell is in transit in the capillary

HbF% = percent fetal haemoglobin.

PS exposure

HaemolysisNO

Platelet activation

Hypoxia reoxygenationInflammation

Endothelial activationCEC

Overexpression TF

Red celldehydration

CEC = circulating endothellial cells; NO = nitric oxide; PS = phosphatidylserine; TF = tissue factor.

Reproduced from Stuart MJ, Nagel RL. Lancet. 2004;364:1343-60 © 2004, with permission from Elsevier.

Modified by M de Montalembert.

Patophysiology

Mark T. Gladwin and Elliott Vichinsky. Pulmonary Complications of Sickle Cell Disease. N Engl J Med 2008;359:2254-65.Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007; 21: 37–47David C Rees, Thomas N Williams, Mark T Gladwin. Sickle-Cell Disease. Lancet 2010; 376:2018-31

Severe formsof SCD

Asymptomatic patients

Intermediate forms

of SCD

Penicillin, folic acid, hydration

Hydroxyurea

Chronic blood transfusion

Bone marrow transplantation

PainACS

Stroke

ACS = acute chest syndrome.

Severity of SCD varies widely among patients

Red blood cellsHbFα-Thalassaemia

EndotheliumNO/ET1

Neutrophils/inflammationAdhesion molecules

Reproduced from Stuart MJ, Nagel RL. Lancet. 2004;364:1343-60 © 2004, with permission from Elsevier.

Modified by M de Montalembert.

Potential modifiers of disease severity

ET1 = endothelin 1.

Clinical manifestations in SCD

CNSInfarctive and hemorrhagic strokesSilent ischemic infarcts ultimately leading to neurological and neurocognitive impairment

Eyes Retinal ischemia, detachments – ‘sickle retinopathy’

CardiovascularAplastic crises lead to severe anemia and cardiac decompensationCardiomyopathy and/or premature coronary artery disease

PulmonaryRecurrent acute chest syndromePulmonary hypertensionChronic sickle lung disease

KidneysInability to concentrate urineProteinuria progressing to nephrotic syndrome and end-stage renal failure

Joints Osteonecrosis (avascular necrosis) of femoral and humeral heads

Legs Chronic ulcers, usually over the medial malleoli

Complications of SCD in children

Castro O, et al. Blood. 1994;84:643-9.Gill FM, et al. Blood. 1995;86:776-83.

Ohene-Frempong K, et al. Blood. 1998;91:288-94.

Polymerization of deoxy-HbS Endothelial dysfunction

Age (years)

Bacteraemia

Pain

ACS

ASS

Stroke

Chronic organ damage ?

1 2 43 65 7 13 14 158 129 10 11

highly variable

ASS = acute splenic sequestration.

Stroke subtype by age

● Ischaemic stroke– 54% of CVAs– highest in 1st decade and

after 30 years– peak at 2–5 years

● Haemorrhagic stroke– during 2nd decade– Risk factors: low Hb, high WBC,

hypertension and steroids use

● Silent stroke– radiological findings consistent

with white-matter disease– 10–30% (not characterized as

age-dependent)– associated with cognitive

deficiencies and higher stroke risk

Verduzco LA, Nathan DG. Blood. 2009;114:5117-25.

Age (years)

Haz

ard

func

tion

0.0010

0.0015

0.0020

0.0025

0.0030

0.0035

0.0040

10 20 30 40 50

Haemorrhagic stroke

Infarctive stroke

CVA = cerebrovascular accident.

DeBaun MR, et al. Blood. 2012;119:4587-96.

Prevalence of silent infarcts60

Prev

alen

ce (%

)

Mean age (years)

0

10

20

30

40

50

0 5 10 15

11.86

27.7 28.2

37.4

Vichinsky E, et al. Pediatrics. 1988;81:749-55.

100

98

96

94

92

90

88

860 10 20 30 40 10

YearsMonths

Surv

ival

(%)

HbSS diagnosed in newborn period

HbSS diagnosed after newborn period

HbSS = haemoglobin SS.

Earlier diagnosis positively impacts survival

Prophylaxis with oral penicillin reduces morbidity and mortality of pneumoccocal

infections

• 125 SCD children aged 3–36 months• Randomly assigned to receive either 125 mg oral

penicillin or placebo

Gaston MH, et al. N Engl J Med. 1986;314:1593-9.

Placebo group

Penicillin group p

Streptococcus pneumoniaeinfections 13 2 0.0025

Death (S. pneumoniae) 3 0 0.003

Incidence of S. pneumoniaesepticaemia 0.09 0.02 < 0.05

Acute Painful Crisis in Sickle Cell Disease

• Acute painful crisis are the most common complication in SCD-> rate of 0.8 episodes per yr.

• Episodes of pain are sometimes trigger by infection, extreme temperatures or by physical, or emotional stress.

• The large part of the acute painful crisis are unprovoked and begin with little warning

Possible Causes of Acute Pain Interesting Bone-Muscle District(s) to be considered

in SCD patients

• Bone infarction

• Aseptic necrosis of bone: ephiphyseal segments of the humari and especially of the femora

• Osteoporosis and vertebral collapse

• Osteomelities

• If pain interests a joint, associated with fever and local signs of arthritis--> consider septic arthritis

Treatmentof complications

● PAIN

● Infections● Acute anaemia: ASS, aplastic crisis● Severe vaso-occlusive events: ACS, strokes, priapism,

organ failure● Pulmonary hypertension● Complications in high-risk pregnancies

Transfusion therapy is a cornerstone for management of SCD complications

ACUTE PAINFUL CRISIS Vaso-occlusion

Patient clinical examination• District identification• Pain pattern: MILD-MODERATE

•Injury•Inflammation•Ischemia•Infarction

Hydrate and

Observe

1st level analgesic therapy

Patient clinical re-examination: pain score at 12-24-48 hrs

Resolution of the acute

painful crisis

UNCHANGED or WORST

PAIN H

PAIN CONTROL STRATEGIES:combined treatments with different

pharmacological targets

• Nonsteroidal anti-inflammatory agents affect pain signal transduction.

• Oppiods influence transmission and modulation of nociception and if used in systemic form can influence pain-perception .

Rees DC. Br J Haematol 120: 744, 2003

PERSISTENT PAINOR SEVERE PAIN

Admission to IM/HematolDepartment

2nd level Analgesic Therapy

Patient clinical examination• District identification• Pain pattern

• CBC (WBC)• X Rays• Bone scan

TransfusionStrategies

pRBCs or TEA

Hydration(i.v.)

at least 2L/d

pRBCs: packed red blood cells; TEA: erythrocytoapheresis

ACS is the most frequent cause of death

Most frequent cause of mortality in adult patients with sickle cell disease!

• 15% artificial ventilation needed• 3% mortality (19% in ICU)

± 50% of sickle cell patients will present with ACS

ICU = intensive care unit. Steinberg MH, Barton F. J Am Med Assoc. 2003;289:1645-51.

Imaging→ Bilateral lower lobes infiltrates more prominent on the right side compatible with ACS

syndrome

Progression of pneumonia in the face of treatment

Acute chest syndrome• A new pulmonary infiltrate involving at least one

complete lung segment not consistent with atelectasis• One or more of

– Chest pain– Fever– Tachypnea, wheezing, cough– Hypoxemia compared with baseline

• Complicates 30% of admissions for painful vaso-occlusive crises

• Most common post operative complication in patients with sickle cell disease

Pathophysiology of ACS in SCD patients

• Causes– infection*– fat embolism– vaso-

occlusion

Rees DC, et al. Lancet. 2010;376:2018-31.RSV = respiratory syncytial virus; Staph. = Staphylococcus; S.pn = Streptococcus pneumoniae.

Vaso-occlusion: increased HbS polymerization

Hypoventilation and atelectasis secondary to rib

and vertebral infarction

ACSPulmonary infection*

Erythrocyte rigidity

Regional hypoxia

Decreased oxygen delivery

Desaturated haemoglobin

Shunting of blood veins to

arteries

VCAM-1

α4β1 integrin

Increased endothelial VCAM-1 expression and adhesion

Increased erythrocyte adhesion in lung-pulmonary infarction

Microvasculature occlusion and bone marrow infarction

Fat embolism

Inflammation: secretory

phospholipase A2

NO

NO

*InfectionChlamydia: 29% Mycoplasma: 20% Staph. aureus: 5%S.pn: 4%Legionella: 2%RSV: 10%

Causes of ACS (1)

• Definite cause was established in 38% of cases– Infection 29%– Pulmonary infarction 16%– Pulmonary fat embolism 9%

• Most common post operative complication• Occurs in 30% of patients hospitalized for

pain– Incentive spirometry effective prevention

ACS clinical course

• Mean length of hospitalization 10.5 days• Patients >20 years of age had a more

severe course than those 20 years of age • Thirteen percent of patients required

mechanical ventilation; 81% recovered • Neurologic events occurred in 11%,

among whom 46% had respiratory failure • One fifth of the patients treated with

bronchodilators had clinical improvement

Causes of death

• Three percent of patients died. The most common causes of death were pulmonary emboli and infectious bronchopneumonia

Management of ACS

• Hydration – Do not over hydrate, use D5 ½ NS– Avoid boluses and overload

• Antibiotics– Third generation cephalosporine: ceftriaxone

or cefotaxime (Clinda for allergic patients)– Macrolide: azythromycin– Consider vancomycin

• Bronchodilators– Asthmatic patients with SCD do poorly

Management of ACS

• Transfusions– Simple transfusions 10 mL/kg packed cells

• Improve oxygenation for hypoxic patients• Anemia• Progression by CXR

– Exchange transfusion for severe patients who have poor response to oxygen

• Pain management• Oxygen