7. KARDİYOPULMONER
BAYPAS
Tarihçe Türkiye
• 1953 ve 1954 İstanbul’da Dr. Nihat
Dorken ve Dr. Fahri Arel : KMK
• 1960 Dr. Mehmet Tekdoğan; İlk KPB
• 1962 Dr. Aydın aytaç, Açık kalp
ameliyatı serisi
TARİHÇE
KPB TEMELİ
AMAÇ
KPB DEVRESİ
KPB BİLEŞENLERİ
KPB MONİTÖRİZASYON
HATLAR
POMPA BAŞLIKLARI
VENÖZ REZERVUAR
OKSİJENATÖR
GAZ SUNUMU:BLENDER
FİLTRELER
ASPİRATÖRLER
VENTLER
PRİME SOLUSYONU
ANTİKOAGULASYON
KANULASYON
METABOLİK DÜZENLEME
23. KARDİYOPULMONER
BAYPAS
Roller pompa
NONPULSATİL PULSATİL
TARİHÇE
KPB TEMELİ
AMAÇ
KPB DEVRESİ
KPB BİLEŞENLERİ
KPB MONİTÖRİZASYON
HATLAR
POMPA BAŞLIKLARI
VENÖZ REZERVUAR
OKSİJENATÖR
GAZ SUNUMU:BLENDER
FİLTRELER
ASPİRATÖRLER
VENTLER
PRİME SOLUSYONU
ANTİKOAGULASYON
KANULASYON
METABOLİK DÜZENLEME
• Hat içerisinde peristaltik
hareket yaratan iki yuvarlayıcı
silindir ile kanın itilmesi
sağlanır
• Önünde pozitif gerisinde
negatif basınç oluşur
• İleri ve geri hareket ile ters
akım iki yönlü akım
yaratılabilir
• Akım dönme hızı ve hat çapı ile
doğru orantılıdır
• Pulsatil veya nonpulsatil akım
oluşturabilir
24. KARDİYOPULMONER
BAYPAS
Centrifugal
(Santrifüjlü) pompaTARİHÇE
KPB TEMELİ
AMAÇ
KPB DEVRESİ
KPB BİLEŞENLERİ
KPB MONİTÖRİZASYON
HATLAR
POMPA BAŞLIKLARI
VENÖZ REZERVUAR
OKSİJENATÖR
GAZ SUNUMU:BLENDER
FİLTRELER
ASPİRATÖRLER
VENTLER
PRİME SOLUSYONU
ANTİKOAGULASYON
KANULASYON
METABOLİK DÜZENLEME
• Dışı kapalı metal rulmanları
olan koni
• Pompaya bağlandığında
manyetik alandan dolayı koni
döner
• Koninin dönmesi negatif basınç
oluşturur ve akımı çekerek
girdap oluşturur
• 2000-4000 devir/dk
• Kan çıkışa doğru yönlendirilir
• Kan akımı basınç gradienti ve sistemik
vasküler rezistans ile ilişkilidir
• Daha az hemoliz ve platelet
aktivasyonu
• Pahalı
• Metal yüzeylerde ısı ve pıhtı oluşumu
25. KARDİYOPULMONER
BAYPAS
Venöz rezervuarlar
• Kalpten 40-70 cm aşağıda
• Yerçekimi veya sifon etkisi ile drenaj
– CVP
– Seviye farkı
– Kanul, hat ve konektör rezistansı
– Sistemdeki hava
TARİHÇE
KPB TEMELİ
AMAÇ
KPB DEVRESİ
KPB BİLEŞENLERİ
KPB MONİTÖRİZASYON
HATLAR
POMPA BAŞLIKLARI
VENÖZ REZERVUAR
OKSİJENATÖR
GAZ SUNUMU:BLENDER
FİLTRELER
ASPİRATÖRLER
VENTLER
PRİME SOLUSYONU
ANTİKOAGULASYON
KANULASYON
METABOLİK DÜZENLEME
26. KARDİYOPULMONER
BAYPAS
Venöz rezervuarlar
• Sert (Açık)
– Polikarbonat çeper
– İçerisinde negatif basınç oluşturulabilir
– Polyester filtre
– Poliüretan köpük eritici
– Sıvı ve ilaç verilmesi için uygun girişler
– Her zaman içerisinde sıvı olmak zorundadır
– Cerrahi alandan gelen aspiratörler
• Yumuşak (Kapalı)
– Negatif basınç oluşturulamaz
– Daha az hava embolisi
TARİHÇE
KPB TEMELİ
AMAÇ
KPB DEVRESİ
KPB BİLEŞENLERİ
KPB MONİTÖRİZASYON
HATLAR
POMPA BAŞLIKLARI
VENÖZ REZERVUAR
OKSİJENATÖR
GAZ SUNUMU:BLENDER
FİLTRELER
ASPİRATÖRLER
VENTLER
PRİME SOLUSYONU
ANTİKOAGULASYON
KANULASYON
METABOLİK DÜZENLEME
35. KARDİYOPULMONER
BAYPAS
Primelama
Prime KPB öncesi devrede dolaşan tüm
sıvıları ifade eder. KPB’a girişte
hemodinamik bozulma ve hava
embolizasyonuna engel olur.
• Boy ve kilo
• Böbrek fonksiyonları
• Hb/Htc
• Kalp büyüklüğü
• Sıvı dengesi
TARİHÇE
KPB TEMELİ
AMAÇ
KPB DEVRESİ
KPB BİLEŞENLERİ
KPB MONİTÖRİZASYON
HATLAR
POMPA BAŞLIKLARI
VENÖZ REZERVUAR
OKSİJENATÖR
GAZ SUNUMU:BLENDER
FİLTRELER
ASPİRATÖRLER
VENTLER
PRİME SOLUSYONU
ANTİKOAGULASYON
KANULASYON
METABOLİK DÜZENLEME
36. KARDİYOPULMONER
BAYPAS
Standart Prime
• 1400–1800 ml, kan volümünün % 30–35
• Hematokrit %30 ancak daha düşük seviyeler de tolere
edilebilir.
– Hastanın büyüklüğü
– Preoperatif Htc
– Pre-KPB kan kaybı,
– Pre-KPB sıvı verilmesi
– KPB Prime volüm
– İdrar miktarı
• Hemodilüsyonu engellemek için rezervuar venöz yoldan
antegrad veya arteriyel sistemden retrograd olarak
hastanın kendi kanıyla (400–500 ml) doldurulabilir.
• Solüsyon heparinlenir
• Membranöz oksijenatör içerisindeki ve arteriyel
hatlardaki tüm hava çıkarılır.
• Bebeklerde kan volümünden fazla olabilir, bu da kan
ilavesi gerektirir
TARİHÇE
KPB TEMELİ
AMAÇ
KPB DEVRESİ
KPB BİLEŞENLERİ
KPB MONİTÖRİZASYON
HATLAR
POMPA BAŞLIKLARI
VENÖZ REZERVUAR
OKSİJENATÖR
GAZ SUNUMU:BLENDER
FİLTRELER
ASPİRATÖRLER
VENTLER
PRİME SOLUSYONU
ANTİKOAGULASYON
KANULASYON
METABOLİK DÜZENLEME
47. KARDİYOPULMONER
BAYPAS
Isınma
• Isı değiştirici ile max 10 °C gradient
• 3 dk 1 °C
• Max ısı 37.5 °C
TARİHÇE
KPB TEMELİ
AMAÇ
KPB DEVRESİ
KPB BİLEŞENLERİ
KPB MONİTÖRİZASYON
HATLAR
POMPA BAŞLIKLARI
VENÖZ REZERVUAR
OKSİJENATÖR
GAZ SUNUMU:BLENDER
FİLTRELER
ASPİRATÖRLER
VENTLER
PRİME SOLUSYONU
ANTİKOAGULASYON
KANULASYON
METABOLİK DÜZENLEME
48. KARDİYOPULMONER
BAYPAS
"The perfect perfusion to me… is to be
allowed to perform the necessary
repair, however long that takes and
yet leaving my patients looking like
they’ve never been on bypass. "
Dr. Norman Shumway
Stanford University
TARİHÇE
KPB TEMELİ
AMAÇ
KPB DEVRESİ
KPB BİLEŞENLERİ
KPB MONİTÖRİZASYON
HATLAR
POMPA BAŞLIKLARI
VENÖZ REZERVUAR
OKSİJENATÖR
GAZ SUNUMU:BLENDER
FİLTRELER
ASPİRATÖRLER
VENTLER
PRİME SOLUSYONU
ANTİKOAGULASYON
KANULASYON
METABOLİK DÜZENLEME
52. MİYOKARDİYAL
KORUMA
«Kalp cerrahisinin başarısı kalbi
ne kadar iyi koruduğunla
ilgilidir.»
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
53. MİYOKARDİYAL
KORUMA
«Kalp cerrahisinin başarısı kalbi
ne kadar iyi koruduğunla
ilgilidir.»
Bilgin Emrecan
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
54. MİYOKARDİYAL
KORUMA
«Kalp cerrahisinin başarısı kalbi
ne kadar iyi koruduğunla
ilgilidir.»
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
55. MİYOKARDİYAL
KORUMA
Tarihçe
• 1950 Bigelow, Hipotermi
• 1955 Melrose, K+
• 1975, Braimbridge, Kristalloid KP
• 1979, Buckberg, Kan KP
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
56. MİYOKARDİYAL
KORUMA
Miyokardiyal koruma (MK)
• Postiskemik miyokardiyal disfonksiyonunu
(Düşük debi, Hipotansiyon) azaltma veya
engellemede kullanılan tüm strateji ve
metodlardır.
• Postiskemik miyokardiyal disfonksiyon
iskemi reperfüzyon hasarından
kaynaklanmaktadır.
– İntrasellüler Ca2+ birikimi
– Reaktif oksijen radikalleri
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
57. MİYOKARDİYAL
KORUMA
Kardiyoplejik olmayan MK
yöntemleri
• Boş atan kalp
• Selektif koroner perfüzyon
• Fibrillatuar arrest
• Sistemik hipotermi <24° C
• Fibrillasyon ve hipotermi
• İntermittan kross klemp
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
58. MİYOKARDİYAL
KORUMA
Kardiyopleji (KP)
• Operasyon esnasında kalbi diyastolik
arrest yaparak iskemi-reperfüzyon
hasarından korumak için verilen
solüsyondur.
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
59. MİYOKARDİYAL
KORUMA
Stratejiler
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
Verilme
yolu
İçerik Isı Aralık İlaveler Monitör İlave stratejiler
Antegrad kristaloid Soğuk Aralıklı Elektrolit Isı Anestezik
Retrograd Kan Ilık Devamlı Farmakolojik pH Normovolemik
hemodilusyon
Konduitler
yoluyla
Mikropleji Sıcak Metabolik nonkardiyoplejik
Entegre Nötrofil deplesyonu
İzkemik koşullandırma
Off pump
60. MİYOKARDİYAL
KORUMA
Miyokard
• Tüm O2’nin %7 ‘sini tüketir.
• İskemide ilk 10 dk da ATP %50 azalır.
Sol ventrikül oksijen kullanımı
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
61. MİYOKARDİYAL
KORUMA
Amaç
• Operasyonda iskemi süresince
miyokardiyal hasarı engellemektir.
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
62. MİYOKARDİYAL
KORUMA
Miyokardın enerji kullanımı
belirleyicileri
• Sol V ED duvar gerilimi (LVEDP)
• Elektromekanik aktivite
• Isı
– Metabolik ihtiyaç azalır
– Metabolizma yavaşlar
– O2 tüketim azalır
– Reperfüzyon hasarı azalır
– Apopitoz azalır
Miyokardın enerji sunumu
belirleyicileri
• Nonkoroner kollateral dolaşım ( 50 ml/dk)
• İntrinsik (glikojen) ve ekstrinsik (Glukoz) substrat
depoları, buffer
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
63. MİYOKARDİYAL
KORUMA KP Bileşenler
• K → Diyastolik arrest, O2 Talebi %80
düşer
• Na → intraselüler ödemi ve Ca’u azaltır
• Mg → Membrane stabilizasyonu, Ca’nun
hücre içine geçisini azaltır, ATP kofaktörü
• Buffer (THAM) → anaerobik glikolizin
optimizasyonu
• Substrat → enerji
• Albumin, Mannitol → Ödemi azaltır
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
64. MİYOKARDİYAL
KORUMA
Kardiyopleji Verilme yolları
Verilme yolu
• Antegrad
– Aort kökü
– Direk koroner
– Safen greftlerine
• Retrograd
– Koroner sinüs
• Ciddi koroner lezyonu
• Aort yetersizliği
– Sağ koroner perfüzyonunda –kısıtlama
• Kombine
Verilme Sıklığı
• Aralıklı
• Devamlı
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
65. MİYOKARDİYAL
KORUMA
Kardiyopleji Isısı
• Soğuk Kristalloid 4 ° C
– Intrasellüler tip : Na, Ca Ø↓
– Ekstrasellüler tip: Na, Ca , Mg↑
• Soğuk kan KP 10–16 ° C
– Kan: kristalloid= 8:1, 4:1, 2:1
• Ilık Kan KP 29 ° C
• Sıcak Kan KP 37 ° C
Ventrikül ısısı (septum) < 15 ° C olmalı
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
67. MİYOKARDİYAL
KORUMA
Kristalloid Kardiyopleji
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
iyon Kristalloid Kan Bazlı St Thomas
Na+ (mmol/l) 144 142
K + (mmol/l) 20 20
Ca 2+ (mmol/l) 2.2 1.7
Mg 2+ (mmol/l) 16 16
HCO 3 – (mmol/l) 0 30-40
Procaine (mmol/l) 1 1
Hematocrit 0 %10-12
Osmolarity (mOsmol/kg
H 2 O)
300–320 310–330
68. MİYOKARDİYAL
KORUMA
Kan Kardiyoplejisi
• Oksijen sunumu
• Hemodilusyonu engeller
• Buffer özelliği
• Osmotik özellik
• Fizyolojik pH
• Endojen antioksidanlar
• Basit ve ucuz
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
69. MİYOKARDİYAL
KORUMA
Substratlı Kan kardiyoplejisi (1:4)
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
İçerik Konsantrasyon
K+ (2 mEq/ml) 16–20 mmol/l
THAM (0.3 mol/l) pH 7.5–7.7
Citrate–phosphate–dextrose 0.2–0.4 mmol/l
Aspartate 13 mmol/l
Glutamate 13 mmol/l
Dextrose 50 <400 mg/l
Dextrose 5% 380–400 mOsm
70. MİYOKARDİYAL
KORUMA
Multi-dose düşük K+ soğuk Kan
kardiyoplejisi (1:4)TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
İçerik Konsantrasyon
K+ (2 mEq/ml) 8–10 mmol/l
THAM (0.3 mol/l) pH 7.6–7.8
Citrate–phosphate–dextrose 0.5–0.6 mmol/l
Dextrose 5% 380–400 mOsm
71. MİYOKARDİYAL
KORUMA
Optimal KP
• Hızlı ve güvenli arrest
• Homojen dağılım
• Asidozu engellemeli
• Enerji üretiminin devamı
• İskeminin zararını engellemeli
• Enerji ve oksijen tüketimi minimum
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
72. MİYOKARDİYAL
KORUMA
Akut MI
• Düşük doz K+
• Ca kanal blokeri
• Substrat
• 20 dk infüzyon
• Lökosit deplesyonu
Hipertrofik kalp (Örn. AS)
• Doz bir buçuk katına çıkılır
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
73. MİYOKARDİYAL
KORUMA
Topikal hipotermi
• Frenik sinir hasarı
• Epikardiyal nekroz
• Diffüz olmayan ısı dağılımı
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
74. MİYOKARDİYAL
KORUMA
Hot Shot
• Reperfüzyon öncesi
• Retrograd 150-200 ml/dk, 32-37 ° C
• 30 ml/kg ,2-4 dk
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
75. MİYOKARDİYAL
KORUMA
İskemik koşullandırma
• Bir iskemi süresine maruz kalındığında
iskemiye karşı gelişen biyolojik
adaptasyonlardır.
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
76. MİYOKARDİYAL
KORUMA
Off-pump MK
• Intrakoroner Shunt
• B-bloker, adenozin
• Stabilizatör
• TA regülasyonu
• Önce proksimal anastomoz
• IABP
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
77. MİYOKARDİYAL
KORUMA
Yenidoğan kalbi
• Enerji kaynağı olarak glukoz kullanır,
glikolitik kapasite yüksek, 5-nukleotidaz
enzimi düşük
• Hipoksiye dayanıklı
• Miyokardiyal su artışına duyarlı (tek doz
kristalloid KP <80 dk veya 20-30 dk)
• İntrasellüler Ca az
• 20-30 ml/ kg induksiyon, 10 ml/kg idame
(20-30 dk’da)
• Kan kardiyoplejisi erişkinlerdekinden
daha az önemli. Uzun iskemide önemli
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
YENİDOĞANDA MK
SONUÇ
78. MİYOKARDİYAL
KORUMA
Sonuç
• İdeal MK yöntemi henüz
netleşmemiştir.
• Kan kardiyoplejisi daha optimal
koruma sağlar.
TARİHÇE
İSKEMİ-REPERFÜZYON
HASARI
KARDİYOPLEJİK
OLMAYAN MK
KARDİYOPLEJİK MK
AMAÇ
MK BİLEŞENLERİ
KARDİYOPLEJİ YOLLARI
KARDİYOPLEJİ ISISI
KARDİYOPLEJİ BASINCI
KARDİYOPLEJİ
ALTERNATİFLERİ
KRİSTALLOİD KARDİYOPLEJİ
KAN KARDİYOPLEJİSİ
OPTİMAL KARDİYOPLEJİ
ÖZEL DURUMLARDA
KARDİYOPLEJİ
TOPİKAL HİPOTERMİ
REPERFÜZYON
İSKEMİK
KOŞULLANDIRMA
OFF-PUMP MK
ÇOCUKTA MK
SONUÇ
Until 1953, cardiac surgery was in its infancy and was more of a curiosity, except for treatment of rheumatic mitral stenosis, beginning in 1923 with Cutler’s successful case of a closed mitral commissurotomy with a tenotomy knife at the Peter Bent Brigham Hospital in Boston.1 The only successful heart operations done before 1953 were closed techniques for mitral stenosis,2 a few clinical experiments in 1952 with “open” heart by deep hypothermic arrest by John Lewis at the University of Minnesota,3 and the “blue-baby” operations of the 1940s and 1950s.4
It is not a fluke that John Gibbon was the first to do this procedure. He had studied and worked tirelessly on this project for 23 years before the first successful application. Dr Gibbon, who would have also celebrated his one-hundredth birthday in 2003, was a medical student at Jefferson and finished his residency in surgery at the Pennsylvania Hospital in the late 1920s. In 1930, he obtained a research fellowship with Dr Edward Churchill, the Chief of Surgery at the Massachusetts General Hospital in Boston. On October 3rd, 1930, Dr Gibbon witnessed the collapse of a patient with a massive pulmonary embolism after a general surgical operation. After a period of deteriorating hemodynamics, watched closely by Dr Gibbon at the patient’s bedside all night, the patient underwent a closed pulmonary embolectomy (Trendelenburg operation) performed by Dr Churchill, but to no avail; the patient died. This dramatic clinical experience had a profound and lasting effect on Dr Gibbon and determined his lifetime academic research interest.5 He labored at the Massachusetts General Hospital and later at Jefferson in attempts to develop a machine that could interrupt the circulation by taking over the functions of the heart and lungs, allowing surgeons to remove a clot from the pulmonary circulation and then restore normal hemodynamics.
There obviously had been no machine like this, but a number of investigators in the early years of the 20th century had been working on isolated animal heart support with oxygenated perfusion, perhaps the most famous being that of Charles Lindbergh working with Alexis Carrel in the 1930s.6 While relatively little had been done to support the circulation in the way that Gibbon foresaw, even the detail of precisely and consistently anticoagulating the blood was a difficult project in the 1930s, though McLean had discovered heparin in 1916.7 Gibbon persisted for 5 years at the Massachusetts General Hospital fabricating pump after pump to support his thesis and then continued his work in Philadelphia at the University of Pennsylvania in the late 1930s. After World War II, during which he was a distinguished military medical officer, Dr Gibbon returned to Penn for a short time and then became Professor of Surgery at his alma mater, Jefferson. He did his clinical work in the morning and his research work in the surgical laboratories in the afternoon to develop his heart-lung machine (without, I might say, the advantage of National Institutes of Health–supported grants).
In the late 1940s, continuing his work on several different versions of the ever-improving heart-lung machine, he contacted the IBM Corporation to collaborate on manufacturing the possible first human version. This occurred because one of his medical students had been very friendly with Thomas Watson, who was then the Chairman of the Board of IBM. IBM worked with him in developing Model I of the heart-lung machine. Though relatively successful in extensive experimentation in animals,8 it was ineffective in supporting the total cardiopulmonary bypass system in volumes large enough to support a human being. Many notable peripheral events related to cardiac surgical techniques and technologies occurred during those 23 years of research. He had to decipher every aspect of artificial circulation we now take for granted: how to drain the blood from the body, how to pump it back, how to clear air from the inside of the heart, how to anticoagulate successfully without clotting the machinery, etc.
After the first IBM model failed to work as well as he had hoped, Dr Gibbon developed a second model in his own laboratory, which was the successful machine that eventually allowed human bypass operations. The final design of Model II (Figure) developed in the early 1950s9 consisted of a screen oxygenator, which allowed blood on both sides of the screen mesh to interface with oxygen, and three roller pumps modified from Dr Michael DeBakey’s original transfusion pump design10 to pump the blood back into the body. The disassembling, cleansing, and sterilization of nondisposable equipment were, of course, critical and laborious parts of the research project.
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Having had increasing success with experiments with total cardiopulmonary bypass in large animals (dogs), Dr Gibbon was now poised to use this technique in human beings. Dr Gibbon did his first human operation in February 1952, using his machine on a 15-month-old girl with an alleged atrial septal defect. At this time, cardiac catheterization was a major event, especially in children, and the patient was too small to have a catheterization before surgery. Unfortunately, this patient died on the operating table because the patient did not have an atrial septal defect but rather a left-to-right shunt through a large patent ductus arteriosis.5
The second operation he performed with his heart-lung machine is the one we celebrate on May 6th as the first successful truly open-heart operation performed with the use of a heart-lung machine. The patient was an 18-year-old woman who had symptoms of right-sided heart failure, and her cardiac catheterization revealed a large left-to-right shunt at the atrial level. On that fateful spring morning, after complete heparinization, the arterial inflow cannula was placed in the left subclavian artery, and the inferior and superior vena cava were cannulated with plastic tubes. All this was done through a large, bilateral submammary incision—the so-called clamshell incision, which lifted up the entire upper thoracic to expose the heart—an incision that is rarely, if ever, used in modern cardiac surgery. After opening the atrium, a large secundum atrial septal defect was encountered, which was closed with a running cotton suture. The patient was removed from the heart-lung machine without incident after approximately 26 minutes. She made an uneventful recovery and was discharged 13 days postoperatively. She was recatheterized 6 months postoperatively, and her defect was completely closed. The case was absolutely astounding to those who witnessed it, as it was to the entire world soon after this first successful case was announced in the press.
Dr Gibbon subsequently operated on 2 additional patients in July 1953, both of whom were young girls about 5 years of age with atrial septal defects. These two patients died at surgery with difficulties again of imprecise diagnosis of atrial septal defect and complications related to bleeding during long time periods on the heart-lung machine.5 After these two cases, Dr Gibbon, quite upset at these failures, declared a moratorium on open-heart surgery with his heart-lung machine. Curiously, Dr Gibbon’s momentous successful case was not published until one year later in a state medical journal, Minnesota Medicine.11
Dr Gibbon never again did open-heart surgery, leaving his trainees and countless others in the field to carry out the prodigious cardiac feats that we all know and take for granted today. He maintained only a research interest in the development of subsequent models of the heart-lung machine, but it was immediately apparent that others in the field, who were primarily interested in cardiac surgery, such as Clarence Dennis of Downstate University in Brooklyn,12 John Kirklin of the Mayo Clinic,13 and C. Walton Lillehei at the University of Minnesota,14 would pick up the gauntlet, refine Dr Gibbon’s original heart-lung machine, and use it extensively. With the improvement of diagnosis and preoperative preparation, uniform anticoagulation, and improved postoperative care, heart surgery blossomed in the late 1950s and early 1960s. Dr Gibbon’s Model II heart-lung machine was the framework on which other applications were modeled. The first truly commercial heart-lung machine was the Mayo-Gibbon device, which was the most widely used heart-lung machine of the 1950s and early 1960s and was developed by Kirklin and coworkers at the Mayo Clinic after the design of Dr Gibbon.13
After the development of the heart-lung machine, Dr Gibbon returned to the active practice of general thoracic surgery, leaving cardiac surgery to others, recalling that his primary interest had always been thoracic surgery and that his sentinel case of pulmonary embolism was a complication of a general surgical operation. He became Professor and Chairman of Surgery at Jefferson and was President of the American Surgical Association in 1954 and the American Association of Thoracic Surgery in 1961. He gave his last talk on the development of the heart-lung machine at Baylor in late 1972 and shortly thereafter passed away in early 1973 at the age of 69 from a fatal heart attack.5
The world owes John H. Gibbon, Jr, MD, an enormous debt of gratitude for pioneering the technology of cardiopulmonary bypass and persisting for 23 years in its development—until he got it just right, on the morning of May 6th, 1953.
Kalp cerrahisinin tıp tarihine girişinden sonra ilerlemesi büyük bir patlama göstermiş olup, sadece yeni tekniklerin gelişmesini sağlamakla kalmamış, aynı zamanda tıp ve teknolojinin hemen her dalında yeni aşamaları da birlikte getirmiştir. Anesteziyolojide, kalp kateterizasyonu ve angiografide, hematoloji ve koagülasyon araştırmalarında, ritim sorunlarının elektrik uyarılarla düzeltilmesi ve pacemaker yapımında, plastik maddelerden yararlanmada ve yeni araçların geliştirilmesinde, doku transplantasyonları için yapılan immünolojik çalışmalarda gösterilen ilerlemeler ve elde edilen başarılı sonuçlar bunlardan sadece birkaçıdır. Hekimliğin tarih içerisindeki gelişiminde kalp her zaman korkuları ve özellikle cerrahi açıdan uzak durulması gereken bir organ olarak algılanmıştır.
16. ve 17. yy’da kalp yaralarına dokunulmaz ilkesi yavaş yavaş gerçekliğini yitirmiştir. 1761’de Morgagni ilk defa otopsi bulgularına dayanarak kalp tamponadını tanımlamıştır. Kalp yaralanmalarının klinik belirti ve patolojileri hakkındaki bilgiler zamanla çoğalmakla beraber bu konudaki tedavi girişimleri gecikmiştir. 1882’de ilk defa Block, tavşan deneylerinde myokardı başarıyla dikebildiğini bildirmiştir. Perikardın başarıyla ilk defa dikilmesi ise, 1891’de Dalton tarafından gerçekleştirilmiştir. 5 yıl sonra da Ludwig Reh, bir kalp yaralanmasında myokardı dikerek hastayı yaşatan ilk cerrah olmuştur. 1896’da gerçekleştirilen bu ameliyat kalp cerrahisinin başlangıcı olarak kabul edilir.
Kalp cerrahisinin gelişimi konusunda Prof. Sherman’ın sözleri dikkate değer: Kalbe olan mesafe sadece birkaç santimetre olduğu halde cerrahi bu yolu ancak 2400 yılda katedebilmiştir [1].
19. yy’ın sonları ile 20. yy’ın ilk yarısında bilim ve teknikteki gelişmelerin doğal bir sonu olarak tıbbın değişik dallarındaki ilerlemeler de kalp cerrahisinin hızlı gelişmesinde büyük rol oynamıştır [2].
1895’de tıpta kullanılmaya başlayan radyografik teknikler kalp cerrahisini büyük ölçüde etkilemiş ve kalp hastalıklarının kesin tanısı kolaylaşmıştır. Modern anestezinin doğuşu intratorasik cerrahi girişimlere imkan sağlamıştır. 1858’de Lord Snow hayvanlarda ilk defa endotrakeal anesteziyi uygulamıştır. İnsanlar üzerindeki ilk başarılı uygulama ise 1869’da Trendelenburg tarafından gerçekleştirilmiştir.
Kardiak girişimlerin emin bir biçimde yapılabilmesini imkan sağlayan önemli bir başka gelişme de kan transfüzyonlarının klinikte uygulanabilir hale getirilmesidir. İlk başarılı kan transfüzyonu 1828’de James Blandell tarafından doğumu takiben ortaya çıkan hemorajik şokun tedavisi için yapılmıştır. Transfüzyon reaksiyonlarının ciddi bir klinik sorun haline dönüşmesinden sonra bu alana yönelik çalışmalar 1900 yılında Karl Landsteiner’ın kan gruplarını bulmasıyla olumlu sonuç vermiştir.
İlk Kalp Ameliyatları
Kalbe ilk başarılı sütürü koyan Ludwig Rhen, konstriktif perikarditin tedavisi amacıyla perikardın soyulması kavramını da geliştiren cerrah olmuştur. 1921’de Almanya’da Rhen ve Schmieden ilk Perikardiyektomi ameliyatlarını başarıyla gerçekleştirmişlerdir. Bu gelişmeler ile cerrahi yavaş yavaş kalbe yaklaşmaya başlamıştır.
Kalp cerrahisinin gelişmesi yönünde atılan adımlardan birisi PDA’nın tedavisi amacıyla cerrahi bir tekniğin geliştirilmesidir. Defektin kapatılması yolunda kadavra araştırmalarına dayanarak önce öneride bulunan 1907’de John Munro olduğu halde ilk başarılı duktus ameliyatı 1938’de Robert Gross tarafından yapılmıştır. Bu tarih kalp cerrahisinin konjenital kalp hastalıklarınnı tedavisine kapılarını açtığı gün olarak kabul edilir. Aynı yıl içinde Gross, Hufnagel ile birlikte Aorta koarktasyonlarının cerrahi tedavisi üzerinde çalışmaya başlamıştı. John Hopkins Üniversitesi’nde ise Alfred Blalock deney hayvanları üzerinde sol subclavian arteri koarktasyonun distaline köprüleyerek bir teknik geliştirmiş fakat iskemik paralizi oluştuğundan insanlarda uygulamaya geçmemişti. 1940’da Clarence Crafoord, bir duktus ameliyatı sırasında gelişen kanamayı kontrol altına alabilmek için aortayı 28 dk. klemplemek zorunda kaldığında hiçbir paralitik belirtinin oluşmaması üzerine koarktasyona direkt yaklaşım için cesaret kazanıp 1944’de birkaç gün ara ile 2 hastada geliştirdiğ uç-uca anastomoz tekniğini başarıyla uygulamıştır. 2. Dünya Savaşı yıllarında John Hopkins Üniversitesi’nde pediatrik kardiolojinin temellerini atan Helen Taussig, Alfred Blalock’a siyanotik olgularda bir şant ile pulmoner akımın artırılabileceği düşüncesini açtı. Bu ikili ortak çalışmaları sonucunda 1944 yılında kendi isimleri ile anılacak olan şant ameliyatını gerçekleştirdiler [3]. Bunu 1948’de Bailey-Harken ve Brock tarafından yapılan kapalı mitral komissürotomi ameliyatları izledi. 1940’larda Toronto Üniversitesi’nde Bigelow, kalp cerrahisinin gelişebilmesi için patoloilerin direkt olarak görülerek tedavi edilmesi gerektiğini düşünmüş ve bu yolda hipoterminin faydalı olabileceğine karar vermişti. Bigelow ilk önce kış uykusuna yatan hayvanları inceleyerek hibernasyon konusunu araştırmaya başladı.
1952’de Minnesota Üniversitesi’nde John Lewis, asistanları Lillhei ve Varco ile birlikte inflow oklüzyon ve hipotermi ile ilk atrial septal defekt ameliyatını gerçekleştirmiştir. Bigelow’un hipotermi tekniğini inflow oklüzyonu ile birlikte 1953’te Colorada Üniversitesi’nde Henry Swan kullanmış ve ilk pulmoner kapak eksizyonu olgusunu gerçekleştirmiştir. 1959’da İngiltere’de Charles Drew ise derin hipotermi ile ilk Ventriküler Septal Defekt ameliyatını yapmıştır. Yeni Zelanda’da Barret-Boyes derin hipotermi ve sirkülatuar arrest ile ameliyat ettiği ilk Fallot tetralojili infant olgularını 20 yıl sonra yayınlayacaktır.
Modern Kalp Cerrahisini Başlatan Adım:Ekstrakorporeal Dolaşım
Modern kalp cerrahisini başlatan adım hiç şüphesiz ekstrakorporeal dolaşımın kliniğe girmesidir. Ancak bu tekniğin uygulanabilmesini mümkün kılan iki ayrı önemli buluş vardır: Bunlardan birincisi kalp kateterizasyon tekniğinin geliştirilmesidir. 1929’da Werner Frossman ilk kalp kateterizasyonunu yapan kişi olarak anılır.1950'de Zimmerman ve ark.ilk kez sol kalp kateterizasyonunu gerçekleştirdiler. Bu teknik 1953’te kateter konması için Seldinger tarafından geliştirilen perkütan yöntem sayesinde kolaylaştırılmıştır. 1959’da Sones ve ark. ilk kez koroner arterler içine radyoopak madde vermiştir. 1962’de Ricketts ve Abrams, 1967’de Judkins bazı perkütan transfemoral koroner anjiografi yöntemleri geliştirdiler.
İkinci önemli buluş ise, heparinin John Hopkins Üniversitesi’nde Mc. Lean tarafından keşfidir. 1930’lu yıllarda saflaştırılarak klinikte uygulamaya başlanan heparinin aynı yıllarda Chargoff ve Olson tarafından protamin ile nötralize edilebileceği gösterildi.
Ekstrakorporeal dolaşım tekniğini kullanarak dünyada ilk başarılı açık kalp ameliyatını John Gibbon yapmıştır. Gibbon 1953’te 18 yaşındaki bir bayan hastada bu tekniği kullanarak atrial septum defektini başarıyla kapatmıştır. Yirmiiki yıl süren bir araştırmanın ürünü olan bu yeni uygulama kalp cerrahisinde çığır açmıştır. Bunu izleyen girişimlerdeki olumsuz sonuçlar Gibbon’ı bu müdahaleden soğutmuştur. Minnesota Üniversitesi’nde Lillehei ve ekibi, 1955’te Mayo klinikten Kirklin, Gibbon pompasında bazı modifikasyonlar yaparak başarılı bir klinik seri oluşturmuştur. Kirklin Kalp-Akciğer makinesını tamamlayarak o zaman bu makinaya üstünlüğü yüzünden Rolls-Royce ismi takılmıştı. Böylece kalp cerrahisi teknolojik gelişmelerden giderek artan oranlarda yararlanmaya başlamıştı. Aynı yıl içerisinde De Wall, Minnesota Üniversitesi’nde köpüklü oksijeneratör geliştirerek klinikte kullanmaya başlamıştı [4]. Açık kalp cerrahisinin gelişmesiyle birlikte konjenital kalp lezyonlarının büyük bir kısmında tam düzelme veya tama yakın düzeltme teknikleri hızla gelişmiştir. 1959’da Senning, büyük arterlerin transpozisyonunda venöz akımın intraatrial düzeyde yönlendirilmesini ilk defa uygulamıştır. 1964’te Mustrad, Senning tekniğini daha da basitleştirmiş ve bu modifikasyon o yıllarda bütün dünyada geçerli olmuştur. 1966’da Ross ve Sommrville, atrezik pulmoner kapağın tedavisi için aortik homogreft by-pass tekniğini kullanmışlardır. Bir yıl sonra da Rastelli, Ongley ve Kirklin trunkus Arteriozusun düzeltilmesinde yeni bir teknik tanımlamışlardır. Bu teknikte bir aorta protezinden yararlanmaktaydılar. Aynı araştırmacılar 1968’de atrio-ventriküler kanal tamiri için yeni bir teknik geliştirmişlerdir. Tek ventrikülün cerrahi onarımı 1972’de Japonya’da Sakaribara tarafından bildirilmiştir. Trikuspit atrezisinin tedavisi ise 1971’de Fontan ve Baudet tarafından yayınlanmıştır.
Kapak Cerrahisi
Carrel ve Tuffier 1914’te yaptıkları hayvan deneylerinin sonucunda aort ve pulmoner kapak stenozlarının da cerrahi olarak tedavi edilebileceğini öne sürmüşlerdir. Tuffier aynı yıl ilk aortik komissürotomi ameliyatını yapmıştır. 2 yıl sonra Sir Henry Souttar, Londan Hospital’da sol atrium’dan parmakla mitral kapağa ulaşarak kapakçıkları kesmeden sadece annülüsü genişletmek suretiyle ilk komissürotomiyi gerçekleştirmiştir. Mitral darlığının transatrial ilk başarılı cerrahi tedavisini Charles Bailey gerçekleştirmiştir. Bu operasyondan kısa bir süre sonra Dwaight Harken aynı tekniği bir valvülotom kullanarak uyguladı. Yine aynı dönemde Londra’da Brock kendisine ait başarılı mitral valvülotomi serisinden kazandığı deneyimle Bailey ve Harken’ın ilkeleri doğrultusunda mitral valvülotomi ameliyatını yapmaya başlamıştır.
Kapalı mitral komissürotomide elde edilen başarılı neticeler mitral kapak yetersizliğinin de cerrahi tedavisine yönelik çalışmalara yol açmıştır. Bu patolojinin giderilmesi amacıyla iki yaklaşım ortaya atıldı. Bunlardan ilki yetersiz durumdaki kapağın çeşitli ek materyallerle desteklenmesi, ikincisi ise anülüsün daraltılmasıyla kapakçıkların birbirine yanaşmasını sağlamaktı. Harken, Jordan, Nichols, Kay, Davila ve Glover bu amaçla çok çeşitli teknikler geliştirmişler. Ancak her defasında kapak yetersizliği yeniden gelişmiştir. Bu nedenle de kapalı tekniklerle mitral kapak yetersizliğinin tedavisi mümkün olmamıştır.
Mitral kapak cerrahisi hızla gelişirken aorta darlığının da cerrahi tedavisi için yeni tekniklerin kullanılmasına başlanmıştı. Kendisi 1950’de Aort stenozundan ölen Horoce Smithy deney hayvanlarında transaortik ve transventriküler valvülotomi teknikleri geliştirmişti. 1950’de Bailey, üçgen biçiminde genişleyebilen bir alet kullanarak apikal yaklaşımla aort kapağı komissürotomisinde oldukça iyi sonuçlar elde etmeye başladı. 1950’li yılların başlarında Charles Hufnagel ve J. Moore Campbell aorta kapağının yetersizliğinin tedavisi için deney hayvanlarında yeni bir yaklaşımla toplu kafes modeli yapay kapaklar geliştirdiler. Campbell, bu kapakları insanlarda hiç kullanmadı. Hufnagel ise 1950’de ileri derecede aort apak yetersizliği olan bir hastada inen torasik aortaya bu yapay kapağı başarıyla yerleştirerek kalp cerrahisinde yeni bir çığır açtı.
1953’te açık kalp cerrahisi klinik uygulamaya girince kapalı tekniklerle tedavisi başarılamayan ve özellikle yetersizliğin hakim olduğu kapak lezyonları için düzeltme teknikleri geliştirildi. 1956’da Lillehei ilk başarılı açık mitral komissürotomi ameliyatını uyguladı. Lillehei, Gott, DeWall ve Varco kısa bir süre sonra açık annüloplastiyi gerçekleştirdiler. Bu tekniklerle hastaların önemli bir kısmında yeterli palyasyon sağlanabiliyordu. Ancak kapak yapısının ileri derecede bozuk, kalsifik veya immobil olduğu hallerde total kapak replasmanının kaçınılmazlığı bu çalışmaların sonucunda iyice açıklık kazandı. Nina Braunwald, 1960’da 5 hastada fleksibl polyurethane yapay kapaklar kullanarak mitral kapağı bütünüyle çıkarmak suretiyle değiştirdiklerini, ancak bu hastalardan dördünü erken dönemde, beşincisini de üç ay sonra kaybettiklerini bildirdi. Aynı yıl içinde Albert Starr, mitral kapağında darlık ve yetersizliği olan 52 yaşındaki bir hastaya Edwards ile beraber geliştirdikleri toplu kafes tipi bir yapay kapak takarak ilk defa mitral kapak replasmanında uzun süreli başarı elde etti ve çok kısa bir üre içerisinde bütün dünyada bu kapak modeli yaygın olarak kullanılmaya başlandı. Harken Hufnagel’in kapağında yola çıkarak yeni bir toplu kapak geliştirmiş ve bunu subkoroner pozisyonda 1963’te bir olguya takmıştır. Bu ilk olgu uzun yıllar yaşamış ve Harken tarafından iki kez perivalvüler kaçak nedeniyle ameliyat edilmiştir.
1962’de ik kez Ross tarafından aortik homogreft konusu gündeme geldikten sonra Hanckock, Barret-Boyes, Binet ve Lonescu domuz ve sığırdan elde edilen xenogreftler üzerinde uzun süre çalışmışlardır. Ancak 1967’de Carpentier, gluteraldehit ile hazırlanmış xenogreftleri başarılı bir şekilde klinik olarak kullanmıştır. Günümüzde homogreftler yaygın bir şekilde kullanılmakla birlikte de büyük ilgi toplamaktadır.
Kardiyopleji
Kalp cerrahisinin temellerinden biri olan kardiopleji konusundaki çalışmalar 1950’lerde [5] başlamıştır. İngiltere’de Melros yüksek potasyum içeren bir solüsyon ile kalbin durdurulup tekrar çalıştırılabilmesi üzerinde çalışmaya başladı. Sealey ise potasyum, magnezyum ve neostigminden oluşan bir solüsyonu deneysel aşamalardan geçirdikten sonra kendi vakalarında kullanmaya başladı. Sealey aynı zamanda kalp cerrahisine ilk defa bu solüsyonlar için kardiopleji terimini kullanan kişidir [6,7]. California’da Shumway perikard boşluğunu soğuk ringer solüsyonuyla devamlı yıkayarak topikal hipotermiyi myokardın korunması yöntemine ekledi.
Yetmişli yılların başlarında Almanya’dan Hacher, Bretschneider ve Kirch kardioplejik solüsyonlara değişik maddeler ekleyerek kardiak arrest sağlamaya çalışmışlardır. Kısa zamanda bu gruptan Bretschneider’ın solüsyonu pek çok merkezde kullanılmaya başlanmıştır.
Cooley ise normotermik şartlarda gerçekleştirdiği basit aort klempi tekniği ile yaptığı ameliyatlarda karşılaştığı iskemik kontraktür durumunu “stone heart” olarak nitelendirmiş ve 1972’de yayınlanmıştır [8]. St. Thomas Hastanesine bağlı Rayne Enstitüsünden Hearse ile birlikte St. Thomas I adı ile anılan solüsyonun sonuçlarını 1976’da yayınlandıktan sonra myokard korunmasının hücresel düzeydeki mekanizmalarına açıklık getirilmeye başlanmıştır. Hearse ile birlikte bu alana büyük katkılarda bulunan bir başka isim de Buckberg’dir. Buckberg, sıcak, soğuk, aralıklı ve devamlı kan kardioplejisi çalışmalarının da öncüsü olmuştur [9].
Solarzona ve ark. Gott’un 1957’de kullandığı retrograd koroner sinüs perfüzyonu tekniğini klinik uygulamaları ile 70’lerin sonunda yeniden gündeme getirmişlerdir. Akins ile 1984’de koroner cerrahisinde kardiopleji kullanmaksızın hipotermik fibrilasyon tekniğini ilk defa uygulamıştır.
Koroner Cerrahisinin İlk Öncüleri: Weinberg ve Beck
Myokardın kanlanmasını artırmak amacıyla yapılan ilk girişim, ileri derecede anginal ağrıları olan bir hastada Jonnesco tarafından uygulanan servitorasik ganglionektomidir. Bu yaklaşımla kardiosensor yolların kesilmesi suretiyle koroner vazodilatasyon sağlanarak koroner kan akımında artış ve dolayısıyla anginal ağrılarda azalma beklenmiştir. Aynı ilkeden hareket ederek perikoroner nevrektomi, aorta pleksusunun kesilmesi ve posterior rizotomi denenmiş ancak bu girişimlerden istenilen sonuçlar elde edilememiştir. Koroner arterlerdeki tıkanıklık sonucunda azalmış olan myokardial kan akımının artırılmasına yönelik çalışmalarda ilk göze çarpan kişi Beck’tir. 1923 yılından itibaren kalbin kollateral dolaşımını artırmak amacıyla perikardial yapışıklıklar yaratmaya çalışmıştır. Bu amaçla pudra, asbest, kum gibi materyaller kullanarak kardioperikardial ilişkiler yaratmış, 1936’da O’shaugenessy aynı amaç doğrultusunda omentumu kullanmıştır. Ancak oluşturulan inflamasyon sonucu gelişen fibröz ve skar dokusu içerisinden kollateral dalların geçmesi mümkün olmadığından bu girişimlerin sonucu da başarısız kalmıştır. Beck daha sonra aort ile koroner sinüs arasında bir fistül yaratarak myokardial kan akımının artırılabileceğini ileri sürerek Beck 2 adını verdiği tekniği uygulamaya çalışmıştır. Çok yüksek olan operatif mortalite bu girişimi de başarısız kılmıştır. Tüm bu olumsuzluklara karşın Beck 1946’da klinik olarak ilk defibrilasyonu başarmıştır.
Montreal’de çalışan hem biyokimya hem de fizyoloji dalında doktora yapmış olan kalp cerrahı Weinberg distali açık olan sol internal mammarian arterin myokardial bir tünel içerisine implante edilmesinin gelişecek kollateraller aracılığıyla myokard dolaşımının artırılabileceği ilkesini savunmuştur.
1950’li yıllarda Murray ve Thal deneysel olarak ilk aorta-koroner bypass çalışmalarına başlamışlardı. 1953’te ise Rusya’da Demikhov köpekte ilk başarılı LİMA-LAD anastomozunu yapmış ve anastomozun patent olduğunu göstermiştir. 1956’da Bailey ekstrakorporeal dolaşım olmadan ilk koroner endarterektomiyi yapmıştır. Endarterektomi 1980’li yılların sonlarına doğru Dudley Johnson’ın yapacağı uzun arteriotomilerle yeniden gündeme gelecektir.
1960’ta Duboist ekstrakorporeal dolaşım ile sifilizli bir olguya sağ koroner endarterektomi yapmıştır. Duboist kalp cerrahisinde Avrupa’daki öncülerden birisi olup ilk başarılı abdominal aort anevrizması ameliyatını da gerçekleştirmiştir. Duboist’in öğrencilerinden birisi de Carpentier’dir.
İnsanda ilk aorta-koroner bypass 1962’de Sabiston tarafından gerçekleştirilmiş, fakat olgu 3 gün sonra kaybedilmiştir. 1968’de Cleveland klinikte Favaloro sağ koroner artere ilk başarılı bypass ameliyatını yapmıştır. Sol internal mammarian arterin anastomozunu ise 1964’te Leningrad’da Kolesov yapmıştır. Green ve Bailey aynı ameliyatı ancak 1968’de gerçekleştirebilmişlerdir. İlerleyen yıllarda arteriel kondüitlerin önemi daha da artarak Carpentier radial arteri, Lytle inferior epigastrik arteri, Pym ve Suma ise gastroepiploik arteri alternatif olarak önermişlerdir.
Elektro-tedavi ve Pacemakerların Gelişimi
1932’de Hyman, asfiksi ile kardiak arrest geliştikdikten sonra göğüs duvarından soktuğu uzun bir çubukla elektrik vererek kalbi tekrar çalıştırmayı denemiştir. Hyman ilk defa bu cihazı kalp pili olarak adlandırılmıştır. 1947’de Beck ve ark. ventrikül fibrilasyonuna giren bir hastaya acil torakomoti, direkt kardiak masaj ve elektroşok uygulayarak açık resüsitasyon tekniğini ilk defa başarıyla kullanmışlardır. Bu 1960’da kapalı teknikle resüsitasyon gelişinceye kadar kliniklerde uygulanmıştır. 1952’de Paull M. Zoll, insanlarda ilk defa durmuş olan ventrikülü elektrikli uyarılarla çalıştırma başarısını göstermiştir. 1961’de Lown kardioversiyon tekniğini geliştirmiştir. 1957’de Werich, Gott ve Lillhei myokarda ilk defa direkt olarak bir elektrod dikip bunu external pacemaker’a bağlayarak kalbin devamlı uyarılmasını sağladılar [10]. 1958’de Elmqvist ve Senning dünyada ilk defa internal pacemaker kullandılar. Bir yıl sonra da Furman ve Schwedel transvenöz endokardial pacemaker tekniğini ortaya koydular.
Transplantasyon
1900’lü yıllarda Rockfeller Enstitüsü’nde Carrel ilk damar anastomozunu yaptıktan sonra organ nakli konusunda çalışmalara başladı. Deneysel cerrahi alanında bir efsane haline dönüşen Carrel 1912 yılında transplantasyon çalışmalarından dolayı Nobel ödülü ile ödüllendirildi. Savaş öncesinde ve sonrasında deneysel cerrahinin pek tanınmayan başka önemli bir ismi olan Demikhov ise Rusya’da köpeklerde heterotopik kalp ve akciğer transplantasyonu üzerinde çalışıyordu [11]. Kolesov ve Demikhov’un kalp cerrahisine yaptıkları katkılar geç de olsa batı dünyasınca kabul görmüştür. 1960’lı yılların başlarında Reemtsma şempanzelerden aldığı böbrekleri insanlara takmaya başladı. Hardy aynı işlemin insanlarda da yapılabileceğini düşünerek bu konuda çalışmalara başlamıştır. 1964’te Hardy terminal dönemde bir koroner olgusunu arrest durumunda kardiopulmoner bypass’a aldıktan sonra transplantasyondan başka bir seçenek olmadığını gördü. Bunun üzerine bir şempanzenin kalbini bu hastaya taktı. Ancak hasta kısa bir süre sonra öldü. Hardy bu ameliyat sonucu dönemin Amerika’sında ve Missisipi’de ırkçılık aleyhtarları ve meslektaşları tarafından acımasızca eleştirildi. Bu gelişmeler üzerine Hardy transplantasyon konusunda çalışmaktan vazgeçti.
Bu dönemde Stanford Üniversitesi’nde Shumway ve ekibi hayvan deneyleri ile kalp transplantasyonunun temellerini atmaya çalışıyorlardı. Bu ekip ile daha önce çalışmış olan Güney Afrikalı cerrah Barnard ülkesine döndükten sonra 3 Aralık 1967’de insanda başarılı kalp transplantasyonunu gerçekleştirdi. İlk olgusunu 18. günde kaybettikten sonra Aralık 1968’de Barnard bir diş hekimine ikinci transplantasyonu gerçekleştidi. İki yıldan fazla yaşayan transplant hastası Barnard’ı büyük bir üne kavuşturdu. Aynı yıl Amerika’da Shumway, Lillehei, Cooley ve Avrupa’da Duboist ilk vakalarını yaptılar.
1971’de Siklosporinin bulunması 1976’da klinik uygulamaya girmesi ile kalp transplantasyonu alanında yeni bir dönem başlamış oldu.
Köpeklerde ilk kalp-akciğer naklinin Neptun tarafından 1953’te gerçekleştirilmesinden sonra 1981’de Reitz insanda ilk kalp-akciğer translantasyonunu gerçekleştirdi.
Sol Ventrikül Assist Cihazları ve Artifisyel Kalp
Artifisyel kalp düşüncesi ile birlikte sol ve sağ kalbin desteklenmesi düşüncesi 1919’da Borenne’nin teorileri ile başlamıştır. Yale Üniversitesi’nde Kuserow abdomene yerleştirilen hidrolik bir pompa ile gerçekleştirdiği hayvan deneylerini 1958’de yayınlamıştır [12].
De Bakey ve Liotta, Crawford ile birlikte bypass’tan çıkamayan olgulara uygulanabilecek bir cihaz üzerinde çalışmaya başladılar. 1963’de aort kapak replasmanından sonra bypass’tan çıkamayan bir olguya ilk sol ventrikül assist cihazını taktılar. Hasta tüm çabalara karşın 4. günde kaybedildi. Cooley 1981’de sol ventrikül assist cihazı taktığı 21 olgusundan ancak üçünde başarılı olabilmişti. Kontrowiz, Pierce, Kirby, Akatsu ve Bernstein gibi bir çok kişi sol ventrikülün desteklenerek yeterli dolaşımın sağlanması düşüncesinden yola çıkarak artifisyel kalbe ulaşmayı düşünüyordu. Cooley kendi ekibi ile geliştirdiği ilk artifisyel kalbi 1969’da sol ventrikül anevrizması bulunan bir koroner olgusuna taktı. Dört gün sonra bu olguya kalp transplantasyonu yapıldı [13]. Böylece assist cihazların ve artifisyel kalbin transplantasyona köprü olacak şekilde kullanılmaları düşüncesi gelişmeye başladı.
21. yy’a girerken kalp cerrahisinin zaman içerisindeki yolculuğunun henüz tamamlanmadığını aksine xenogreftler, artifisyel kalp ve minimal invaziv girişimlerin olduğu yeni alanlara doğru yol aldığını görmekteyiz.
Türkiye’de Kalp Cerrahisinin Tarihçesi:
Türkiye’de modern kalp cerrahisinin ilk adımları kapalı mitral komissürotomi ile başladı. 1953 ve 1954 yıllarında İstanbul’da Dr. Nihat Dorken ve Dr. Fahri Arel, Ankara’da Dr. Orhan Mumin ve Dr. Hilmi Akın bunun öncülüğünü yaptılar. Daha sonraları Dr. Dorken ve Dr. Akın kapalı komissürotomi ve perikardiektomi ameliyatlarını büyük seriler halinde uyguladılar.
Ülkemizde ekstrakorporeal dolaşım kullanmak suretiyle ilk açık kalp ameliyatı teşebbüsü 1960 yılında Dr. Mehmet Tekdoğan tarafından Hacettepe Üniv. Hastanesi’nde gerçekleştirilmiştir. Seri halindeki açık kalp ameliyatlarında ise Dr. Aydın aytaç tarafından 1962 yılında Hacettepe Çocuk Hast.’de başlandı. Hipotermi ve inflow oklüzyon tekniği ile açık kalp ameliyatlarına ait ilk klinik uygulamalar birbirinden müstakil olarak Dr. Dorken ve Dr. Aytaç tarafından 1962 yılında İstanbul’da Milli Türk Tıp kongresinde tebliğ edildi. Ekstrakorporeal dolaşım ile yapılan açık kalp ameliyatına ait Türkiye’de ilk tebliği ise; 1963 yılında Dr. Aytaç tarafından Bursa’da toplanan Milli Türk Tüberküloz ve Toraks Kongresinde yapıldı [14] ve aynı yıl içinde, Hacettepe Tıp merkezindeki 100 Konjenital kalp ameliyatı sonuçları yayınlandı [15]. İngiliz doktorları Wooler, Nixon ve Grimshow Haydarpaşa göğüs Cerrahisi merkezinde 1963 yılında Dr. Siyami Ersek ve arkadaşlarıyla beraber 2’si başarılı 4 açık kalp ameliyatı yaptılar. 5 Mayıs 1963’te Hacettepe Çocuk Hast.’de Dr. Aytaç ve ekibi tarafından Fallot Tetralojili bir çocukta Total Korreksiyon ameliyatı gerçekleştirildi [16]. Aynı yıl sonunda Dr. Ersek ve ark. Haydarpaşa’da seri halinde açık kalp ameliyatı uyguladılar ve Türkiye’de ilk defa yapay kapak taktılar. Bunu takiben 2 yıl içinde Dr. Ersek ve Dr. Kemal Beyazıt ülkemizdeki ilk çift kapak ve üçlü kapak replasmanını yaptılar. Açık kalp cerrahisinde bu aşamalar süratle ilerlerken ABD’den 2 yıl sonra ülkemizde ilk kalp pili ameliyatı Dr. Aytaç tarafından 1962 yılında gerçekleştirildi ve 66 yaşında Adam Stokes sendromlu bir hastaya sol torakotomi ile Medtronic-Chardack pacemaker takıldı. 1966 yılında ilk insandan insana kalp nakli amileyatının Dr. Barnard tarafından gerçekleştirilmesinden sonra onu takip eden yıl içinde Dr. Bayezid Ankara’da Yüksek İhtisas Hast.’de ve 2 gün sonra Dr. Ersek İstanbul Göğüs Cerrahisi Merkezinde teknik yönden başarılı 2 kalp nakli yaptılar. 1967 yılında heterogreft kalp ameliyatları yine aynı merkezde gerçekleştirildi.
1969 yılında Dr. Aytaç’ın başkanlığında Hacettepe’de Türkiye’nin ilk Pediatrik Kalp Cerrahisi Departmanı kuruldu [17]. En ağır komleks konjenital patolojilerden biri olarak kabul edilen transpozisyon 1970 yılında ülkemizde başarıyla ameliyat edildi [18]. Mustard tipi bu ameliyat yıllarca uygulandıktan sonra yerini Senning ameliyatı aldı [19]. 1974 yılı Şubat ayında ülkemizdeki ilk koroner by-pass ameliyatı Dr. Aytaç tarafından safen ven kullanılmak suretiyle bir bayan hastada başarıyla uygulandı [20]. Türkiye’de seri halinde ve bol sayıda koroner by-pass ameliyatlarını yerleştirmek ise Yüksek İhtisas Hastanesi’nde Dr. Beyazıt ve ark. tarafından gerçekleştirildi [21].
Ülkemizde ilk başarılı Fontan tipi ameliyat Björk modifikasyonu olarak 1980 yılında Hacettepe’de Dr. Coşkun İkizler tarafından uygulandı. Transpozisyonda ise anatomik tamir olan Arterial Switch ameliyatı başarılı olarak İ. Ü. Kardioloji Enst.’den Dr. Tayyar Sarıoğlu tarafından gerçekleştirildi. Dr. Cevat Yakut’un başkanlığında bilhassa erişkin kalp cerrahisinde büyük seriler halinde başarılı ameliyatlar uygulanan Koşuyolu Hast.’de Türkiye’de ilk olarak ameliyattan sonra uzun süre yaşayan kalp nakli, aradan çok uzun yıllar geçtikten sonra Dr. Yakut ve Dr. Ömer Beyazıt tarafından 1989’da yapıldı. Bunu Hacettepe Hast.’de Dr. İlhan Paşaoğlu tarafından yapılan fakat akut rejeksiyonla erken dönemde kaybedilen olgu izledi. Daha sonra yine Hacettepe’de Dr. Bozer ve Dr. Paşaoğlu tarafından 5 kalp nakli ameliyatı daha yapıldı. İnsandan insana kalp nakli ülkemizde tekrar canlanırken Ankara’da İbni Sina Hast.’de Dr. Hakkı Akalın ve ekibi tarafından ilk mekanik kalp başarıyla takıldı (1988). Hastanın hayatta olduğu 4 haftalık süre içinde donör bulunamadığından kalp nakli gerçekleştirilemedi. Daha sonra aynı ekip tarafından başka bir hastaya ortopik kalp nakli 1990’da gerçekleştirildi. Daha sonra Gazi Tıp Fak. Hastanesi’nde Dr. Emin Özdoğan ve Dr. Ali Yener tarafından fresh Aortik Homogreft uygulaması gerçekleştirildi. Ülkemizde ilk başarılı Video Eşliğinde Toraks Cerrahisi (VATS) Uygulamaları 1995’te Dokuz Eylül Tıp Fakültesi’nde Dr. Öztekin Oto ve ekibi tarafından gerçekleştirilmiştir. Yine aynı Üniv.’de 8.1.1998’de Türkiye’de ilk kez Kalp ve Akciğer transplantasyonu, 17 Haziran 1999’da iki taraflı akciğer transplantasyonu Dr. Oto ve ekibi tarafından gerçekleştirilmiştir.
Türkiye’de Kalp Cerrahisinin Tarihçesi:
Türkiye’de modern kalp cerrahisinin ilk adımları kapalı mitral komissürotomi ile başladı. 1953 ve 1954 yıllarında İstanbul’da Dr. Nihat Dorken ve Dr. Fahri Arel, Ankara’da Dr. Orhan Mumin ve Dr. Hilmi Akın bunun öncülüğünü yaptılar. Daha sonraları Dr. Dorken ve Dr. Akın kapalı komissürotomi ve perikardiektomi ameliyatlarını büyük seriler halinde uyguladılar.
Ülkemizde ekstrakorporeal dolaşım kullanmak suretiyle ilk açık kalp ameliyatı teşebbüsü 1960 yılında Dr. Mehmet Tekdoğan tarafından Hacettepe Üniv. Hastanesi’nde gerçekleştirilmiştir. Seri halindeki açık kalp ameliyatlarında ise Dr. Aydın aytaç tarafından 1962 yılında Hacettepe Çocuk Hast.’de başlandı. Hipotermi ve inflow oklüzyon tekniği ile açık kalp ameliyatlarına ait ilk klinik uygulamalar birbirinden müstakil olarak Dr. Dorken ve Dr. Aytaç tarafından 1962 yılında İstanbul’da Milli Türk Tıp kongresinde tebliğ edildi. Ekstrakorporeal dolaşım ile yapılan açık kalp ameliyatına ait Türkiye’de ilk tebliği ise; 1963 yılında Dr. Aytaç tarafından Bursa’da toplanan Milli Türk Tüberküloz ve Toraks Kongresinde yapıldı [14] ve aynı yıl içinde, Hacettepe Tıp merkezindeki 100 Konjenital kalp ameliyatı sonuçları yayınlandı [15]. İngiliz doktorları Wooler, Nixon ve Grimshow Haydarpaşa göğüs Cerrahisi merkezinde 1963 yılında Dr. Siyami Ersek ve arkadaşlarıyla beraber 2’si başarılı 4 açık kalp ameliyatı yaptılar. 5 Mayıs 1963’te Hacettepe Çocuk Hast.’de Dr. Aytaç ve ekibi tarafından Fallot Tetralojili bir çocukta Total Korreksiyon ameliyatı gerçekleştirildi [16]. Aynı yıl sonunda Dr. Ersek ve ark. Haydarpaşa’da seri halinde açık kalp ameliyatı uyguladılar ve Türkiye’de ilk defa yapay kapak taktılar. Bunu takiben 2 yıl içinde Dr. Ersek ve Dr. Kemal Beyazıt ülkemizdeki ilk çift kapak ve üçlü kapak replasmanını yaptılar. Açık kalp cerrahisinde bu aşamalar süratle ilerlerken ABD’den 2 yıl sonra ülkemizde ilk kalp pili ameliyatı Dr. Aytaç tarafından 1962 yılında gerçekleştirildi ve 66 yaşında Adam Stokes sendromlu bir hastaya sol torakotomi ile Medtronic-Chardack pacemaker takıldı. 1966 yılında ilk insandan insana kalp nakli amileyatının Dr. Barnard tarafından gerçekleştirilmesinden sonra onu takip eden yıl içinde Dr. Bayezid Ankara’da Yüksek İhtisas Hast.’de ve 2 gün sonra Dr. Ersek İstanbul Göğüs Cerrahisi Merkezinde teknik yönden başarılı 2 kalp nakli yaptılar. 1967 yılında heterogreft kalp ameliyatları yine aynı merkezde gerçekleştirildi.
1969 yılında Dr. Aytaç’ın başkanlığında Hacettepe’de Türkiye’nin ilk Pediatrik Kalp Cerrahisi Departmanı kuruldu [17]. En ağır komleks konjenital patolojilerden biri olarak kabul edilen transpozisyon 1970 yılında ülkemizde başarıyla ameliyat edildi [18]. Mustard tipi bu ameliyat yıllarca uygulandıktan sonra yerini Senning ameliyatı aldı [19]. 1974 yılı Şubat ayında ülkemizdeki ilk koroner by-pass ameliyatı Dr. Aytaç tarafından safen ven kullanılmak suretiyle bir bayan hastada başarıyla uygulandı [20]. Türkiye’de seri halinde ve bol sayıda koroner by-pass ameliyatlarını yerleştirmek ise Yüksek İhtisas Hastanesi’nde Dr. Beyazıt ve ark. tarafından gerçekleştirildi [21].
Ülkemizde ilk başarılı Fontan tipi ameliyat Björk modifikasyonu olarak 1980 yılında Hacettepe’de Dr. Coşkun İkizler tarafından uygulandı. Transpozisyonda ise anatomik tamir olan Arterial Switch ameliyatı başarılı olarak İ. Ü. Kardioloji Enst.’den Dr. Tayyar Sarıoğlu tarafından gerçekleştirildi. Dr. Cevat Yakut’un başkanlığında bilhassa erişkin kalp cerrahisinde büyük seriler halinde başarılı ameliyatlar uygulanan Koşuyolu Hast.’de Türkiye’de ilk olarak ameliyattan sonra uzun süre yaşayan kalp nakli, aradan çok uzun yıllar geçtikten sonra Dr. Yakut ve Dr. Ömer Beyazıt tarafından 1989’da yapıldı. Bunu Hacettepe Hast.’de Dr. İlhan Paşaoğlu tarafından yapılan fakat akut rejeksiyonla erken dönemde kaybedilen olgu izledi. Daha sonra yine Hacettepe’de Dr. Bozer ve Dr. Paşaoğlu tarafından 5 kalp nakli ameliyatı daha yapıldı. İnsandan insana kalp nakli ülkemizde tekrar canlanırken Ankara’da İbni Sina Hast.’de Dr. Hakkı Akalın ve ekibi tarafından ilk mekanik kalp başarıyla takıldı (1988). Hastanın hayatta olduğu 4 haftalık süre içinde donör bulunamadığından kalp nakli gerçekleştirilemedi. Daha sonra aynı ekip tarafından başka bir hastaya ortopik kalp nakli 1990’da gerçekleştirildi. Daha sonra Gazi Tıp Fak. Hastanesi’nde Dr. Emin Özdoğan ve Dr. Ali Yener tarafından fresh Aortik Homogreft uygulaması gerçekleştirildi. Ülkemizde ilk başarılı Video Eşliğinde Toraks Cerrahisi (VATS) Uygulamaları 1995’te Dokuz Eylül Tıp Fakültesi’nde Dr. Öztekin Oto ve ekibi tarafından gerçekleştirilmiştir. Yine aynı Üniv.’de 8.1.1998’de Türkiye’de ilk kez Kalp ve Akciğer transplantasyonu, 17 Haziran 1999’da iki taraflı akciğer transplantasyonu Dr. Oto ve ekibi tarafından gerçekleştirilmiştir.
Mitral kapak protezinin konulmasından önce iki belirgin teknikle mitral darlığı açılıyordu : I.Komüssürotomi, II. parmak dilatasyonu. Elliot Cutler ile Samuel Levine ilk komüssürotomi ameliyatını Eylül 1923 te, Bostonda Peter Bent Bringham Hospital’de gerçekleştirdiler. Onlar kendi yaptıkları işleme valvotomi, kullandıkları alete valvotom dediler. Ancak işlem sonucu kapak yetmez hale gelebiliyordu.
Parmak dilatasyonu (genişletmesi), mitral kapak darlığını açmak için kullanılan belli başlı iki teknikten ikincisiydi. Burada parmakla ya da bir bıçakla kalsifiye olmuş mitral kapak açılıyordu. Peter Bringham Hospital’de Sir Henry Souttar, 1923 te, ilk parmakla genişletme operasyonunu yapmıştır.
Souttar’ın çalışması, Charles Bailey, Harken ile Ellis’in 1948 de, birbirlerinden habersiz olarak yaptıkları parmakla dilatasyonun yeniden keşfine(!) kadar gölgede kaldı, bilinmedi. Bailey yaptığı ameliyata komüssürotomi adını verdi. Harken ile Ellis te valvoplasti dediler. Her iki girişim de 25 yıl önce Souttar’ın yaptığıyla aynıydı. Sonraları Smitty, Murray ile Brock bu yöntemlerin değişik biçimlerini geliştirdiler. Ama bazı kapaklar çok kötü biçimde daralmış oluyordu; çözüm bunların değiştirilmelerinde (replacement ) yatıyordu.
F. John Lewis ile Walton Lillehei, 2 Eylül 1952 de, yüzeyel soğutma + hipothermi kullanarak 5 yaşında bir kızın kalb defektini tamir ettiler. Aynı cerrahlar bu iş için cross circulation yöntemini de denemişlerdir.
Judson Cheesterman, 22 Temmuz 1955 Cuma günü, İngiltere Sheffield General Hospital’de ilk kez mitral konumda bir top’lu yapay kapağı, kapalı yöntemle yerleştirdi. Kapak Perspex’ten yapılmıştı, bir dış kafesi vardı. Bu kafes bir puppet (patlarlı motorların süpaplarında olduğu gibi vertikal yönlendirici) gibi çalışıyordu. Kapağı dışardan sıkıştırmak için iki düğmesi vardı. Hasta 14 saat yaşadı. Ölüm nedeni puppet’in dönerek yerinden fırlamasıydı.
Dr. Frank F. Allbritten, 1953 te, sol karıncık için bir vent geliştirdi. Bununla kalb içi hava komplikasyonlarını çözümlüyordu. Ama bu kalb vent’i durdurulmuş kalbde kanın dolup sol karıncığı aşırı şişirmemesi için de işe yaramıştır.
DeBakey‘in yönetiminde Houston grubu 1950 lerin sonlarında sistematik olarak, assending aorta rezeksiyonu ile graft replasmanıyla ilgili operasyonlar geliştirdiler. Bu ameliyatlarda kardiopulmoner bypass kullanıldı. Ilgili makale JAMA dergisinde 1956 da yayınlanmıştır. Aslında arcus aorta 1957 yılına kadar cerrahların bıçağından uzakta kalmıştır. Ta ki Houston grubu başarıyla bir arcus aorta anevrizmasını çıkarıp yerine arcus aorta homograftı yerleştirinceye kadar. Makale Surgery of Gynecology and Obstetric degisinde 1957 de yayınlandı.
Dr. Willem Kolff ile Tetsuzo Akutsuz, 1957 de, Cleveland Clinic’te, bir köpeğe ilk yapay kalbi taktılar. Hayvan 90 dakika yaşamıştır.
Denton Cooley ile ark. , 1957 de, kardiopulmoner bypass kullanarak, akut myokardial infarktus’tan sonra gelişen bir interventriküler septum yırtılmasını ilk kez tamir ettiler. Hasta önce iyiydi. Ancak bazı komplikasyonlar yüzünden 6 hafta sonra öldü. Cooley ile ark. 1959 da, bir sol ventrikül anevrizmasını ilk kez rezeke ettiler.
W.P. Longmire jr. ve ark. koroner arterlerin daralmasında endarterektomiyi (damarın tıkanmış bölümünün iç yüzünden çıkarılıp alınması) beş hastada uygulayarak 1958 yılında yayınladılar. Bu hastalardan dördü yaşamıştır. Sonradan bazı gruplarca bu ameliyat uygulandı. Ölüm oranı yüksek bulunduğundan, izole bir ameliyat olarak, terkedildi.
Longmire jr, 1958 de ilk kez koroner arter ile mammaria interna arteri arasında anastomozu gerçekleştirdi. Ne var ki, Longmire’in bu başarısı1990 da Shumacker ile yaptığı bir kişisel iletişime kadar gölgede kaldı, bilinmedi. Aradan tam 32 yıl geçmişti; gerçeği Shumacker açıklığa kavuşturmuş oldu.
Boris Petrovsky, önde gelen bir Rus cerrahı, 1959 da, sol ventrikül anevrizmasında diyafragmadan aldığı pediküllü bir flap’ı kalbin sikatrize olmuş yüzeyine çepeçevre dikerek bu bölgenin fazla gerilmesini önledi. Operatif mortalite yüzde 20 idi. Petrovsky sonradan bu yöntemi terketti. Bununla ilgili makaleleri 1959 da Chest Surgery (Moskova), 1959 da Surgery (Moskova), 1960 da Surgery (Moskova), 1961 de Journal of Thorasic and Cardiovascular Surgery, 1961 de Surgery (Moskova) degilerinde yayınlanmıştır.
İlk başarılı aortik kapak replasmanı Dr. Dwight Harken ile ark. tarafından bir kafes-top tipi kapak kullanılarak yapıldı. Buna ait makale Journal of Thoracic and Cardiovascular Surgery dergisinde 1960 yılında yayınlanmıştır. J.R. Jude, kardiolog, 1961 de, kalbi yeniden çalıştırabilmek amacıyla eksternal kalb masajı yapmayı başardı.
Aynı yıl A.S. Starr ile Lowell Edwards, kendi tasarımları olan bir kafes-top tipi yapay kapağı mitral konumda yerleştirdiler. Dr. Starr genç bir cerrah, Mr. Edwards 65 yaşında deneyimli bir mühendisti, o güne kadar 63 ün üzerinde buluşa imza atmıştı. Gönlünde yatan esasta bir yapay kalb üretmekti. Ancak Dr. Starr onu bir yapay kapak konusunda ikna etmişti. Dr. Starr gerekli olan anatomi, kalb fizyolojisi bilgisiyle kapak replasmanı için gerekli olan cerrahi beceriyi sağladı. Mr. Edwards da mekanik konusundaki becerisini ortaya koyarak yapay kapağı iki yıl içinde gerçekleştirdiler. 1967 yılına kadar yaklaşık 2000 tane Starr-Edwards kafes-top kapağı replasmanı yapılmıştır.
E. H. Sharp, ilk kez, kardiopulmoner bypass kullanarak, açık-kalb yöntemiyle, pulmoner embolektomi ameliyatı yaptı. Bununla ilgili makale Annals of Surgery dergisinde 1962 yılinda yayınlanmıştır. Bilindiği gibi pulmoner embolektomiye ilk kez Frederic Trendelenburg girişmiş olup buna ilişkin klasik makale 1908 de yayınlanmıştır.
Starr ile ark., 21 Şubat 1963 Perşembe günü üç kapak, aortik-mitral-triküspit kapakları replasmanını aynı hastada gerçekleştirdiklerini bildirdiler. Bu dünyada ilk üçlü replasman oluyordu.
Kronolojik olarak sırası gelmedi, ama hemen söyleyelim, Mayo Clinic’ten C.J. Knott-Craig ile ark. 1992 de, bir karsinoid yayılmada, dört kalb kapağını birden, aorta – mitral – tricucpit -pulmoner, başarıyla değiştirdiler.
Yıl 1963 e geldiğinde, Türkiyede ilk açık-kalb ameliyatları, İstanbul Göğüs Cerrahisi Merkezi ile Hacettepe Üniversitesi kalb cerrahisi bölümünde bir kaç gün arayla başlatıldı. Hacettepedeki ekibin başında Dr. Aydın Aytaç bulunuyordu. Bu gün Türkiyede, bir çok merkezde, yılda toplam 15 000 – 20 000 arasında açık-kalb ameliyatı yapılmaktadır. Dünyada ise bu sayı 650 bin dolaylarındadır. Bu, günde yaklaşık 2 000 ameliyat demektir.
Koroner arter cerrahisinde (coronary bypass) modern tekniklerin oluşumu, radyolojik tanı tekniklerinin gelişimini bekledi. Bu bekleyiş bir raslantı sonucu ortaya çıkan bir buluşla sona erdi. Cleveland Clinic’ten bir çocuk kardiolojisti olan Dr. F. Mason Sones, 1958 yılında bir akşam üstü, hastasının aorta kapağını incelemek üzereyken kateter yanlışlıkla sağ koroner arter ağzına girer. Sones hatayı farkedip kateteri geri çekmek ister. Lakin bu sırada 30 cc kadar radioopak madde sağ koroner arter içersine enjekte edilmiş, radyografi çekilmiş olur. Sones bir komplikasyon olarak ventriküler fibrilasyon olmasını bekledi. Ama hiç bir şey olmadı. Ayrıştırıcı bir zekaya sahip olan Sones birden kararını verdi, koroner arterlerin kontras maddeyi tolere edebileceğini keşfetmiş bulunuyordu. Bundan sonra koroner arterleri görünür hale getirebilmek için kateterler tasarımladı, teknikler geliştirdi. 1962 yılında da bu tekniği E.K. Shirey ile birlikte hayata geçirdi. Ne var ki tarihte ilk arter kanülasyonunu 1731 de bir atın karotis arterine kanül koyup buradan arteryel kan basıncı alan fizyolog Stephen Hales yapmıştır.
Dr. David Sabiston,1962 de, Duke Üniversitesinde, ilk kez safen veni ile koroner arter bypass’ını gerçekleştirdi. Bu ilk olgu beyin embolisi yüzünden öldü. Dr. Sabiston 1974 e kadar resmi olarak tekniğini yayınlamadı.
Donald N. Ross, 1967 de, Ross Proseduru diye bilinen aorta kapağına otograft olarak hastanın kendi pulmoner kapağının takılmasını gerçekleştirdi. İlgili makale Lancet degisinde 1967 yılında yayınlanmıştır.
Dr. Lester Sauvage,1963 te, hayvanlarda vena ile yapılan direkt koroner arter bypass’ını yayınladı.
Garret, Dennis, DeBakey, 23 Kasım 1964 Pazartesi günü, aorta ile koroner arterin LAD (left anterior decending) dalı arasında bir vena graftıyla bypass yaptılar. Bu belki Dr. Sabiston’dan sonra başarılan ilk vena bypass’ıydı. Ama yazarlar bunu yayınlamadılar. Makaleleri 1973 te JAMA dergisinde yayınlanmıştır. Hasta bu tarihe kadar yaşamaktaydı. Yapılan anjiografik incelemeler vena graftının açık olduğunu gösteriyordu.
Türkiyede ilk anjiografi, 1963 te, Prof. Dr. Cemi Demiroğlu ile Muhlis Tuzlacı tarafından yapıldı, Bir kitap halinde yayınlandı. Aynı yıl İstanbul Göğüs Cerrahisi Merkezi’nde de, yapılan açık-kalb ameliyatlarının bir gereği olarak, anjiografi işlemi başlamıştı.
Dr. Yalçın Güran ile Dr. Kemal Bayazıt, 1965 te, ilk kez kalb-akciğer makinasıyla, kay-cross doner diskli film oksigenator kullanarak ekstrakorporeal hayat desteğini uyguladılar. 6 saat sonra desteği durdurmak zorunluğu başgösterdi. Hasta kaybedildi.Zira eldeki oksigenator bu işe yetmiyordu.
Georges E. Green,1965 te, ilk kez kardiyopulmoner bypass’la kardiopleji ile 2x büyüteç kullanarak, mamaria interna ile LAD (sol ön inen koroner dalı) arasında anastomoz yaptı Aynı yıl C.P. Bailey ile T. Hirose de mammaria interna-LAD arasında, “minivascular” dikiş tekniği kullanarak, anastomoz gerçekleştirdiler. Ancak Bailey ile Hirose atan kalbde bypass’ı gerçekleştirdi. Buna karşılık Green ekstrakorporeal dolaşımla, sol ventrikül venti koyarak, aortaya cross-clamp uygulayarak ameliyatı yaptı.
Vassily Ivanovich Kolessov,1966 da, Sovyet Rusya’ın Leningrad kentinde, altı olguda angina pectoris’i tedavi için, arterya mammaria interna ile yaptığı koroner arter bypass ameliyatlarını yayınladı. Bunlardan biri ölmüş, beşi yaşamıştır. Ameliyatlar sol torakotomiyle, ekstrakorporeal dolaşım ile sineanjiografi kullanılmadan yapılmıştır. Buna ilişkin makale Journal of Thorasic and Cardiovascular Surgery dergisinde 1967 de yayınlandı.
İstanbul Göğüs Cerrahisi Merkezinde, 1966 yılında, bir hastanın üç kapağı birden değiştirildi. Bu kapaklar aorta, mitral, triküspit kapaklarıydı. Ameliyatı Dr. Kemal Bayazıt yaptı. Bu ameliyat ABD den üç yıl sonra, dünyanın geri kalanında ilk kez yapılmış olan üçlü replasmandır.
Dr. Rene Favoloro Cleveland Clinic’te çalışan bir Arjantinli ile Effler, Mayıs 1967 de, bacaktan alınan safen veniyle yaptığı koroner bypass’lara ilişkin küçük bir hasta grubunu yayınladı.
Dr. Rene Favoloro, 1968 de, mammaria interna arteri ile LAD (left anterior decending = sol ön inen koroner arter) arasında anastomoz yaparak koroner bypass gerçekleştirdi.
Kalbin kapakları üzerinde, ayrıca doğuştan olan anomalileri düzeltmek için gerekli girişimler yapılıyor, başarılı da oluyordu, ama kalbin tümüyle iflas etmiş olduğu olgularda ne yapılabilirdi? Kalbin görevini tümüyle üzerine alabilecek yapay kalb fikrini ilk kez, 1966 da, Huston, Texas’ta Michael DeBakey ortaya attı. Lakin kalb cerrahisi değişik bir yöne gitme eğilimindeydi. Böbrek nakilleri 1963 tenberi, bağışıklık sisteminin reddetme yolunda verdiği cevabı bastırmak için kullanılan immunosupressiv ilaçlar ile, başarıyla yapılmaktaydı. Kalb cerrahisi neden bu yolu seçmesin?
Gerçi, Alexis Carrel ile Charles Guthrie, 1905 te köpekte, 1906 da kedide kalb ile akciğerin beraberce transplantasyonunu yayınladılar; daha sonra Demikhov’un da bu konuda çalışmaları vardır. Fakat insanda ilk kalb nakli girişimi Missisipi Üniversinden J.D. Hardy ile ark. tarafından yapılmıştır. O sırada insan donöründen organ elde etme olanağı olmadığından, büyük boy bir şempanze’nin kalbi donör kalbi olarak kullanıldıysa da, bu kalb dolaşımı sağlayamadı. Hardy’nin bu konudaki makalesi JAMA dergisinde 1963 yılında yayınlandı.
Richard Lower ile Norman Shumway, bu gün de uygulanmata olan kalb transplantasyonu tekniğini ortaya koydular. Alıcının sağ ile sol atriumundan bir manşet ile atrial septumun bir bölümünün yerinde bırakılarak kalbin çıkarılmasından ibaret olan bu tekniği, İngilterede Brock ile Sovyetler Birliğinde Demikhov da tarif etmişlerdir, ama bu tekniğin popüler hale gelmesi Shumway ile Lower’in 1960 da makalelerini yayınlamalarıyla gerçekleşmiştir.
Dr. Christian Barnard, 3 Aralık 1967 Pazar günü, Guney Afrika Cumhuriyeti, Cape Town’daki Groote Schuur hastanesinde, motosiklet kazasında ölen 23 yaşındaki bir kadının kalbini orta yaşlı bir adama nakletti. Dünyada ilk insandan-insana kalb nakli olan bu olguda nakledilen kalbin reddedilmesini (rejecion ) önlemek için verilen güçlü preparatlar nedeniyle hastanın savunma sistemi (immune system ) aşırı baskı altına alındığından 18 gün sonra hasta pnömoniden öldü.
Kalbi değiştirilen ikinci olgu ABD de Adrian Kantrowitz tarafından ameliyat edildi. Bu olgu sadece 6 saat yaşadı, kanama komplikayonuyla kaybedildi. Fakat Barnard’ın 2 Ocak 1968 Salı günü, ilk olgunun ölümünden 12 gün sonra, yaptığı ikinci kalb nakli 18 ay yaşayarak kalb hastaları için bir umut oldu.
Francis Fontan,1968 de, triküspid atrezisi+tek ventrikül+Pulmoner atrezi olgularında Fontan proseduru denilen, üst vena kava ile pulmoner arter arasında pencere açmak ya da ikisi arasına bir “conduit” koymak anlamına gelen ameliyatı ilk kez yaptı. Makalesi Thorax dergisinde 1971 yılında yayınlandı. Kavo-pulmoner anastomoz tekniğini ilk kez N.K. Galankin 1957 de teklif etmiş olup makalesi 1957 yılında Rusyada yayınlanmıştır.
Dr. Yalçın Güran, Ekim 1968 de, İran’ın başkenti Tahran’da üst üste yaptığı beş başarılı açık-kalb ameliyatıyla İrandaki ilk açık-kalb ameliyatlarını başlattı.
Dr. Kemal Bayazıt ile ekibi, Dr. Yalçın Güran’ın da katılımıyla , 1968 yılinda Ankara Yüksek İhtisas Hastanesinde, Türkiyedeki ilk kalb naklini gerçekleştirdi. Bundan dört gün sonra Istanbul Göğüs Cerrahisi Merkezinde, Dr. Siyami Ersek ile ekibi bir kalb nakli yaptılar.
Kalb nakliyle ilgili bu cerrahi başarılar kısa ömürlüydü. 1971 yılına kadar yapılan ilk 170 olgunun 146 sı ölmüştü.
Bir Amerikalı cerrah, Dr. Norman Shumway yoluna devam edebildi. Bu cerrah, bilginler, doktorlardan oluşan bir takımı biraraya getirerek, doku reddinin karmaşık biolojik problemine bilimsel çare aradı. Bu takım, red ataklalarını önlemek için, kalbe bir kateter yerleştirdiler. Bunun içinden kalb kasından ufak bir parça alıp reddolma belirtisi var mı diye incelediler Yalnızca red belirtisi görüldüğünde tehlikeli immunosupressivlerin dozunu arttırdılar. Sonunda Shumway dünyanın öteki yanında yapılan bir kaşiften yararlandı.
Norveç’in Hardaanger fiyordu topraklarında bir fungus bulundu. Bu fungusta kalb nakli cerrahisinde devrim yapacak bir madde, cyclosporin, vardı. Bu madde enfeksiyona karşı direnci büsbütün yıkmadan doku reddini önleyebiliyordu.
Dr. Shumway’in ellerinde cyclosporin kalb nakli alıcılarının talihini değiştirdi. Ama gene de bir güçlük vardı. Kalb nakli bekleyen hastalara kolayca verici bulunamıyordu.
Sonradan cyclosporin’in yanında FK506, ATG, OKT3, MMS gibi preparatlar ile vücut radyasyonu gibi yöntemler bulunup kullanılmaya başlandı.
H. Bentall ile A. De Bono, 1968 de, assandan aorta replasmanını, aortik yapay kapak ile koroner ağızlarını anastomoze ettikleri dakron graft kullanarak yaptılar. Bu dakron grafta, aorta yapay kapağını da içerdiği için kompoze graft dediler. İlgili makale 1968 yılında Thorax dergisinde yayınlanmıştır.
Kalb naklini gerektirecek kadar hasta olan kalblerin yerini alabilecek bir düzenek (yapay kalb) akıllara gelmeye başladı. Daha önce değiştirilecek kalbe bir destek olarak (left ventricular assist device ), sol ventriküle yardım edecek bir aparat tasarlandı. Bundan maksat, kalbi değiştirilecek kimsenin elverişli bir verici bulununcaya kadar hayatta kalmasını sağlamaktı. Yapay kalb, önceleri esas kalbin yerini alıp yaşamı böylece sürdürmeyi sağlayacak bir düzenek olarak düşünüldü. Fakat sonradan yapay kalb de , sol ventriküle yardımcı olan cihazlar gibi, elverişli bir vericinin ortaya çıkması için geçecek zaman boyunca hastayı yaşatabilmek için kullanıldı. Ancak bazı olgularda, ventrikül yükünün azaltılması sonucu, ventrikül kası kendini toparlayabiliyor, hiç bir yardımcıya gereksinme duymadan ya da kalbin dağiştirilmesine gerek kalmadan normal çalışmasına devam edebiliyordu. Elbette bu sonuç, gerçekleşmesi istenilen en iyi sonuçtur.
Yapay kalblerin geçmişi 1950 li yıllara kadar geri gider. Bir grup bilgin, Hollandalı Dr. Willem Kolff’un başkanlığında, tasarımını yaptıkları yapay kalbin potansiyel problemlerini saptamak için bunu hayvanlara uyguladılar. Denton A. Cooley, 4 Nisan 1969 Cuma günü, Huston USA da, ilk yapay kalbi bir hastaya taktı. Bu yapay kalbin tasarımını Dr. Domingo Liotta yapmıştı. 47 yaşında bir hastaya uygulanan yapay kalb hastanın yaklaşık üç gün yaşamasını sağladı. Bu arada uygun bir verici bulundu, hastanın kalbi diğer bir insanınkiyle değiştirildi. İşte daha ilk olguda bile yapay kalblerin öteki sol ventrikül yardımcı aparatları gibi kullanılabileceği akla gelmeye başladı.
Texas Heart Institute’den O.Howard Frazier “Bir gün çalışacak bir kalb pompası yapmak kolay iştir, fakat haftalarca, hatta yıllarca çalışabilecek bir pompa geliştirmek… İşte bu mucizedir.” demiştir.
Doç. Dr. Cemil Barlas, 1969 yılında, Istanbul Üniversitesi Çapa Hastanesi II Cerrahi Kliniğinde, Çapa hastanesindeki ilk açık-kalb ameliyatını başarıyla gerçekleştirdi.
Kalıcı olarak kullanılabilecek yapay kalb için gelişmeler 1982 yılı içinde başladı. Utah Üniversitesinden Dr. William DeVries Jarvik-7 adlı yapay kalbi bir hastaya uyguladı. Ameliyat sırası ile sonrasında bir dizi problem yaşandıktan sonra hasta 112 gün hayatta kalabildi. Jarvik-7 yapay kalbi Robert K. Jarvik geliştirmişti. Bunun doğal kalbde olduğu gibi iki ventrikülü vardı. Diske benzer bir makanizmayla içeri doğru çalışan kapakçıklardan kanı alıp dışarı doğru çalışan kapakçıklara doğru basıyordu.
Bir sol ventrikül yardımcı aparatı olarak (intraaortic baloon pump )Texas Heart Institute’de 1968 de Dr. Adrian Kantrovitz tarafından uygulanmaya başlandı. Bu, bacaktan femoral arter içinden aorta köküne kadar gönderilen balonlu kateterdi. Elektronik olarak, balon, kalb atışlarıyla senkronlandırılmıştı. Buna bağlı olarak balon CO2 ile şişip sönerek kanın akışını kesiyor ya da serbest bırakıyordu. Intraaortik balon pompasının başlıca fizyolojik etkisi, sol ventrikül afterload’ını düşürmek, aorta kökündeki basıncı arttırmak, koroner perfüzyon basıncını yükseltmektir. Bu kavram daha önce de1953 te, gene A.Kantrovitz tarafından, sistolik basıncı geciktirerek koroner kan akımını arttırmak üzere bir köpek deneyinde gösterilmiştir.
Daha sonra, 1962 de, S.D. Maulopulos, S. Topaz ile W.J. Kolff ta benzer bir aparatı ürettiler. Prensip ile çalışma biçimi aynıydı. Yalnız bu kere balon kateter desandan aortaya konulmaktaydı.
Bir de sol ventrikül gibi çalışan left ventricular assist device’ lar yapılmıştır. Bunlarda esas bir silindirik pompa, bu pompadan çıkan üç boru vardır. Bunlardan biri sol ventrikül içine, ötekisi aorta köküne yerleştirilir. Üçüncü boru bir hava kompresörüne bağlıdır. Silindirik pompanın içinde kanı bir yöne gönderecek kapaklarla kan ile havayı birbirinden ayıran esnek bir zar vardır. Basınçlı havanın etkisiyle kan bölmesine doğru itilen zar kana basınç yaparak aorta köküne doğru yol almasını sağlar. Böylece ventrikülün ileri doğru basacağı kanı bu cihaz üzerinden aortaya gönderildiğinden kalbin yükü azaltılmış olur. Demek ki bu alet sol ventriküle mekanik olarak yardım ederek yükün bir bölümünü kendi üzerine almış olur.
İlk ventricular assist device Dr. Michael E. DeBakey tarafından geliştirilmiş, hastaya 1966 yılında uygulanmıştır. İlk takılan cihazın pompası vücut dışındaydı. Bundan çıkan iki borudan biri vücut içine girerek sol ventriküle, öteki de aortaya yerleştirilmışti. Daha yenilerinde pompa ve iki kan borusu karın boşluğuna yerleştiriliyordu. Kompresöre giden, gerekli itici gücü sağlayan boru vücut dışına çıkıyordu. Içerde bir makina ile ilişkili olup gövdenin dışına çikan bu boruların birer enfeksiyon nedeni olabileceğini akıldan çıkarmamak gerekir.
Ekstrakorporeal Hayat Desteği, kardiopulmoner bypass’ın bir uzantısıdır. Başlangıçta kardiopulmoner bypass 6 saati geçmeyen bir zamanla sınırlıydı. 1960 lı yıllarda membran oksigenatorun bulunmasıyla daha uzun süre hayat desteği sağlama olanağı elde edilmiştir. Donald Hill ile ark., 1972 yılında, künt travmaya bağlı olarak şok akciğeri oluşmuş bir 24 yaşındaki bir hastayı bu yolla tedavi ettiler. Hastaya 75 saat membran oksigenatorlü bir kalb-akciğer makinasıyla hayat desteği verilmiştir. Hasta femoral vena ve femoral arterden kanüle edilmişti. Sonuçta hasta iyileşti. Hill’in ikinci olgusuna 5 gün süreyle hayat desteği verilmiş ve hasta iyileşmiştir.
Ankara GATA Hastanesinde düzenli, başarılı bir biçimde açık-kalb cerrahisi uygulaması, Dr. Kemal Bayazıt’ın yardımı, katkılarıyla, 1969 da başladı.
Sterling Edwards, 1972 – 1975 yılları arasında, koroner cerrahisinde bypass graftı olarak 15 olguda splenik arteri kullandı. Daha sonra aynı yazar sağ gastroepiploik arteri, aynı iş için kullanmaya başladı.
Alain Carpentier, 1973 yılında, RA (radial arter) i koroner bypass için graft olarak kullanıma soktu. Fakat sonradan ilk bir yıl içinde yaklaşık % 35 e varan bir tıkanma (occlusion ) oranı saptadığı için bu grafttan vazgeçti.
Dr. Kemal Bayazıt, 1974 te, Ankara Yüksek İhtisas Hastanesinde, Türkiyedeki ilk koroner bypass amliyatını gerçekleştirdi.
Earle Kay’in, 1974 yılında, her iki mammaria interna arterini kullanarak yaptığı koroner bypass ameliyatlarına ait büyük bir olgu serisi vardır.
Biomedicus firması Bio-Pompayı (Sentrifugal) 1975 yılında klinik uygulamaya sundu.
İnsanda Kalb ile akciğerin beraberce transplantasyonu, Standford Üniversitesinden B. A.Reitz ile ark. tarafından 1981 yılında başlatıldı. İlk hasta, ameliyat sonrası, cyclosporine, azothioprine kombinasyonuyla sağıtıldı. Hasta transplantasyondan 5 yıl sonrasına kadar gayet iyiydi. Reitz’in klinik başarısı, önceden primatlarda allograft kullanarak yaptığı deneylere dayanmaktadır. Bu konulardaki makaleleri Journal of Thorasic and Cardiovascular Surgery (1980) ve New England Journal of Medicin (1982) adlı dergilerde yayınlanmıştır.
Türkiyede koroner bypass ameliyatlarında, graft olarak mamaria interna arterini ilk kez Dr. Kemal Bayazıt, Ankara Yüksek Ihtisas Hastanesinde, 1983 yılında kullandı. 1985 yılına kadar mammaria interna ateri, bu hastanede, koroner cerrahisinde ara sıra kullanılırken daha sonra standart graft olarak uygulanmaya konulmuştur.
Dr. Kemal Bayazıt ile ekibi, 5 Şubat 1985 Salı günü, İstanbulda Koşuyolu Kalb ve Araştırma Hastanesini kurarak açılışını yaptılar. O zaman Hastanenin adı Koşuyolu Astım Hastanesiydi. Şimdiki ismini sonradan aldı. Bu hastane özellikle, o güne kadar İstanbulda yapılamıyan koroner cerrahisini uygulamak için kurulmuştu.
Dr. Alain Carpantier ile Dr. Juan Chachques,1985 te, Paris l’hopital Broussais’de latisimus dorsi kasını , kan dolaşımını koruyarak, pedikülü ile alıp yetmez olan kalbin çevresine sararak bir cardiomyoplastie ameliyatını gerçekleştirdiler. Bu kası kalbin kasılması ile senkron olarak elektrikle 30 Hz frekansla uyardılar. Bu metodun kullanılması, bir iskelet kası olan latisimus dorsi’nin yorulması ile sınırlıdır. Zira, bilindiği gibi, iskelet kasları, yapı farkı yüzünden, kalb kası gibi sürekli bir biçimde çalışamaz.
Dr. Alain Carpantier, bunun dışında, mitral kapağı yetmezliğinde kapağı yapay bir kapakla değiştirmek (replacement ) yerine bunu tamir eden metodların öncüsü olmuştur. Replasman yerine tamiri seçmenin nedeni yapay kapağın sonradan birçok güçlüğü de beraberinde getirmesidir. Yetmez mitral kapağının tamiri metodunu kullanım geçtiğimiz yüzyılın son 1/3 ünde artmıştır. Geoffrey Wooler‘in de bu konuda, 1962 yılında Thorax dergisinde bir yayını vardır.
Dr. Kemal Bayazıt, Ankara GATA Hastanesinde ilk kez, anlaşmalı, programlı biçimde koroner arter cerrahisini 1989 da başlattı.
Prof. Dr. Cemi Demiroğlu, 1990 yılı ilkbaharında, Florance Nightingale Hastanesini kurdu. Bu hastanenin kadrosunda Dr. Cihad Bakay, Dr. Bingür Sönmez, Dr. Rüstem Olga, Dr. Aydın Aytaç, Dr. Tayyar Sarıoğlu ile aneztezi servisinin başında da Dr. Osman Bayındır bulunuyordu. Bu kadro 1985 te Kardiyoloji Vakfı (Cerrahpaşa Tıp Fakültesi) nde ameliyatlara başlamıştı. Sonradan Florence Nightingale Hastanesine transfer oldular. Bu hastane Türkiyedeki 4000 hastane içinde ilk 10 a girmeyi başarmıştır. Ancak 1995 ten sonra Dr. Aydın Aytaç İstanbul Amerikan Hastanesine geçerek orada açık-kalb ameliyatlarını yapmaya başladı. Dr. Bingür Sönmez de Dr. Tayyar Sarıoğlu’nun Memorial hastanesinde kurduğu cerrahi servisine transfer olmuştur. Bu günlerde Dr. Tayyar Sarıoğlu, Dr. Bingür Sönmez dışında, ekibiyle birlikte Acıbadem Hastanesine geçmiş bulunuyorlar.
C. Acar, 1992 yılından başlayarak, Alain Carpentier tarafından 1970 li yıllarda kullanılıp terkedilen RA koroner bypass graftı için yüzgüldürücü sonuçların bildirilmesiyle, RA graftları rutin kullanıma soktu.
Türkiyede ilk kez çalışan kalbde koroner bypass ameliyatı, ekstrakorporeal dolaşım kullanılmadan, Ankara Yüksek İhtisas Hastanesinde Dr. Kemal Bayazıt tarafından, 1993 yılında, gerçekleştirilmiştir.
Brezilyada Dr. Randas Batista, 1994 te, kalbi değiştirmek yerine, yeni bir tekniği önerdi. Bilindiği gibi , kalbi değiştirmeye götüren, yetmez hale gelen sol ventriküldür. Kalbin bu odası o kadar genişler ki artık kuvvetle kasılıp kanı ileri, aorta içine atamaz hale gelir. Dr. Batista yetmez hale gelen, aşırı genişlemiş sol ventrikül duvarının uygun genişlikte bir bölümünü kesip çıkarttı. Geriye kalan sol ventrikül duvarı kenarlarını karşılıklı dikti. Böylece ventrikül hacmi ufalmış oldu. Bu işleme Sol ventrikülü küçültme ya da Batista prosedur’u denilmektedir.
Batista’nın öne sürdüğü bu tekniğin haberi yavaş yavaş yayıldı. Az sayıda cerrah bunu denedi. Sonuçlar iyi ya da kötü yönde yorumlanabilecek kadar, şimdilik, çok değildir. Bu tekniğin kalb cerrahisinde bir kilometre taşı olup olmadığına karar için daha biraz zamana gereksinim vardır.
Koroner bypass ameliyatları için Türkiyede RA (radial arter) graftını, ilk kez Dr. Haldun Karagöz 1998 yılında kullanmıştır.
Ilk kez S.R. Gundry tarafından, koroner bypass cerrahisinde uygulanmak için, tam sternotomy (sternum kesisi) yerine değişik bazı sternotomy tipleri 1990 lı yılların ikinci yarısında tanımlanmıştır. Bunlar mini sternotomy, J ya da T sternotomy gibi kesi bıçimleridir. Bunlara minimal invaziv yaklaşımlar adı da verilmektedir.
Türkiyede, aynı zamanda dünyada ilk kez (rib cage sternotomy ), kaburga kafesi sternum kesisini, 1997 yılında Dr. Haldun Karagöz tanımlayıp uygulamıştır. Aynı Türk cerrahı 1998 de, ülkemizde aynı zamanda dünyada ilk kez genel aneztezi yerine lokal anestezi ile hasta uyanıkken koroner arter cerrahisini başarıyla uygulamıştır. Aynı cerrah “subxiphoid” yaklaşımla minimal invaziv mitral kapak cerrahisi ile gene minimal invaziv yaklaşımla assandan aorta anevrizması replasmanını gerçekleştirmiştir.
Daha sonra Didier Loulmet ile Alain Carpentier koroner arter bypass’ını endoskopik yolla bazı robotik aletlerin yardımıyla yaptıklarını 1999 yılında, Journal of Thoracic and Cardiovascular Surgery degisinde yayınladılar. Bu oldukça ilgi çekici bir yöntem olup, önce kadavra üzerinde alıştırma yapıldıktan sonra gerçekleştirildiği bildirilmiştir. Yazarlar bunun koroner bypass cerrahisinde yeni bir alan açtığını söylemektedirler. Robotik araçların işe karıştığı bu yöntem çok yakın gelecekte kalb cerrahisi alanına yerleşeceğe benzer. Şimdiden Türkiyeye bu yöntemi getirmek için çalışmalar başlamıştır. Paskal A. Berdat ile ark., Bern’de bulunan İsviçre Cardiovascular Center’inde 1994-1999 yılları arasında yaptıkları kateter içersinden ASD ya da patent foramen ovale’nin kapatılması girişimlerinden sonra ortaya çıkan komplikasyonları inceledikleri bir makaleyi Journal of Thoracic and Cardiovascular Surgery degisinde 2000 yılında yayınladılar. Buna göre yukarda belirtilen yıllar arasında 124 olguyu bu yolla sağıtmışlar. Bunların % 8 inde komplikasyonlar görüldüğünden açık-kalb ameliyatı uygulaması gerekmiş. Bildirildiğine göre en sık görülen problemler geriye bir shunt kalması, aparatın yerinden çıkması, vasküler komplikasyonlarmış.
S v O 2
During CPB S v O 2 is an indicator of the matching of DO 2 and VO 2 . As the margin between systemic O 2 delivery and demand narrows, O 2 extraction increases and S v O 2 is reduced. Reduced depth of anesthesia or degree of muscular paralysis by muscle relaxant drugs, low inspired oxygen concentration in the fresh gas fl ow mixture or anemia ll decrease S v O 2. However, if these parameters have been optimized, low S v O 2 values generally indicate hypoperfusion and should prompt an increase in pump fl ow rate to improve oxygen delivery. If the ability to increase fl ow is limited by venous return, then increasing DO 2 by increasing HCT, or reducing VO 2 by reducing temperature, is indicated. However, the S v O 2 value should always also be interpreted in the context of core temperature. Th e solubility and hemoglobin binding affi nity of oxygen increases with hypothermia, whilst organ metabolic demand decreases, resulting in increased S v O 2 if perfusion is adequate. Venous saturations of 65–75% are typical at temperatures of 37–35°C, 76–85% at temperatures of 34–32°C, and 85–100% at temperatures of 32–16°C .
2A5.1 : Occlusion of the arterial pump if a roller pump is used:
(a) Clamp the arterial line and any re-circulating lines and close the sampling ports
(b) The pump is carefully turned until the pressure on the gauge is around 300 mmHg and the rate of fall of pressure can be observed
(c) Tighten the occlusion until there is no fall of pressure in this high-pressure range (this ensures that there are no other leaks in the circuit and that all clamps are competent)
(d) Adjust the occlusion until the fall off of pressure over the lower 260–280 mmHg range takes approximately 10 seconds
(e) Both rollers must be treated individually. Should the occlusion between rollers be obviously unequal, the pump should be changed
2A5.2 : Occlusion of the suction pumps
(a) A clamp is placed on the negative side of the sucker boot and the pump is turned until the boot collapses with the vacuum created
(b) The occlusion should now be “backed off ” until the vacuum is cleared
(c) The occlusion setting is then again increased, until the vacuum is just drawn and held
(d) In order to check the direction of rotation of the sucker/vent roller pumps, a small quantity of heparinized saline or other appropriate fl uid should be used by the scrub nurse to check the suction
Principles of Oxygenator Function: Gas Exchange, Heat Transfer, and Operation
Alfred H. Stammers
Cody C. Trowbridge
Although the term cardiopulmonary bypass (CPB) can denote a variety of meanings, in its purest form it describes the circumvention of the native heart and lungs with extracorporeal devices. The primary components are the circulation device, termed the pump, and the gas exchange device, termed the oxygenator. In traditional CPB the pump moves the systemic venous blood, either from the venous reservoir or by direct aspiration, through the oxygenator and then to the arterial side of the circulation. The fundamental purpose of the oxygenator is to arterialize venous blood by removing excess carbon dioxide and increase the partial pressure of oxygen (Po2). However, the oxygenator performs a number of functions that go beyond simple gas exchange. Oxygenators are complex devices made up of distinct components such as membrane modules, heat exchangers, and reservoirs. In fact, oxygenators are capable of performing many functions of the native lung except for endocrine and biologic transformation of humoral factors. Furthermore, they make up the greatest percentage of the total synthetic material used in the extracorporeal circuit, and represent the largest surface area to which circulating blood is exposed. Due to the importance of the oxygenator, they have undergone significant modification over the last five decades to improve performance and reduce the inflammation associated with foreign surface exposure. Oxygenators must perform flawlessly during each procedure in which they are utilized, with devastating consequences encountered when they fail. Therefore, the CPB circuit contains a number of safety features and monitoring capabilities to ensure that the devices are adequately functioning. This chapter will describe the elements of the oxygenator and the performance of these safety devices during extracorporeal circulation.
OXYGENATOR PRINCIPLES
Although the term oxygenator has been used for as long as extracorporeal circulation and CPB have been clinically applied, a more correct description would be a blood gas exchange device, because carbon dioxide, oxygen, and nitrogen are all regulated by its function. However, due to the common application of the term oxygenator, it will be utilized throughout this chapter. Modern oxygenators are almost universally of the membrane type, which employ a semipermeable barrier that separates fluid from gas phases. Therefore, the diffusive qualities of the membrane material determine the transfer of oxygen and carbon dioxide between phases. However, the earliest oxygenators exchange gases through the direct interaction of gas and blood. These devices were used during the advent of CPB and used extensively from the 1950s through the 1970s. Terms such as rotating disk, drum, screen and bubbler were all used to describe the oxygenation devices that used the technique of a direct blood-to-gas interface for gas exchange. Bubble oxygenators were the first widely available commercial oxygenators. However, there were numerous problems associated with percolating, or bubbling, gas through blood and bubbler oxygenators disappeared from clinical use in the United States by the 1990s (1). Currently there are few cardiac surgical procedures being performed anywhere in the world that utilize a direct blood-to-gas system; therefore discussion of these devices will be limited primarily to the historical description provided in Chapter 1.
Oxygenators can be categorized by two uses, with each defined by the length of time the device is anticipated to be utilized. The use of oxygenators for long-term support (>6 hours) is described as either extracorporeal life support (ECLS) or extracorporeal membrane oxygenation (ECMO). Short-term devices (<6 hours) are described as traditional CPB oxygenators. Traditional CPB oxygenators have integral heat exchangers, while ECLS/ECMO oxygenators may have external heat exchangers located distal to the oxygenator. Due to the unique physiology of complete extracorporeal circulation, there is a potential for maldistributed flow between organ beds during CPB. Therefore, most cardiac surgical procedures employ some P.48
level of hypothermia during extracorporeal circulation to protect underperfused regions from ischemic damage. The use of a heat exchanger, connected to a heater-cooler device, effect the temperature changes commonly used during CPB. A second major capability of the oxygenator is blood volume regulation. Most oxygenators are sold with a venous reservoir that may be either a hard-shell (noncollapsible) or soft-shell (collapsible) variety. The latter will collapse upon itself when emptied, reducing the risk of air being pumped to the patient if the reservoir inadvertently empties. Both systems allow the sequestration of excess volume (i.e., volume from the decompressed heart) and provide a mechanism for rapid replacement of lost volume. A final capability of oxygenators, related to gas transfer, is the ability to administer volatile anesthetic gases.
As seen in Chapter 1, early oxygenators were complex and relied upon vast amounts of surface area and a direct blood-to-gas interface to function. The pioneering work by C. Walton Lillehei et al. from the University of Minnesota in the late 1950s made “bubbler” oxygenators both disposable and cheap, and they were easily made from simple components (2). This served the purpose of advancing cardiac surgery because of the ease in which they were applied, and led to the spread of surgery outside the few specialty hospitals that were performing cardiac surgery. However, the “bubbler” design made these devices impractical for all but the shortest of perfusion procedures. With the improvement in safety and biocompatibility of membrane oxygenator, the annual worldwide use of disposable oxygenators has been estimated at approximately 1 million devices.
There are essential considerations in the design of an oxygenator. Gas exchange is the first feature engineers consider, with the movement of carbon dioxide and oxygen being paramount. The ventilating gas of oxygenators can be manipulated by the use of a mixture of medical grade air, oxygen and, in some situations, carbon dioxide. Regulation of the gas mixture is through the ventilation components of the heart-lung machine, which include a gas blender, a flowmeter, an inhalation anesthesia canister, an oxygen monitor, and associated tubing. The quantities of these gases are measured in the circulating blood by the use of in-line monitoring systems or by intermittent sampling of arterial and venous blood samples (3,4). Secondary considerations in oxygenator design include flow characteristics to minimize blood trauma but still minimize the priming volume and surface area of the device (i.e., the amount of liquid that must be added to fill the oxygenator before operation). The oxygenator heat exchanger must also efficiently transfer heat energy. Finally, the composition of the oxygenator is manipulated to limit bioactivation due to foreign surface exposure. Most of these engineering goals are inversely related, creating a formidable design challenge.
TABLE 1 Comparison of Physical Characteristics of a Membrane Lung and Natural Lung
Characteristic
Membrane Lunga
Natural Lungb
Surface area (m2)
0.6—4
70
Blood path width (µm)
200
8
Blood path length (µm)
250,000
200
Membrane thickness (µm)
150
0.5
Maximum O2 transfer (mL/min, STP)
400—600
2,000
a Data for a Medtronic ECMO membrane oxygenator (Medtronic Cardiopulmonary, Inc., Minneapolis, MN). b Guyton AC. Textbook of medical physiology. Philadelphia: WB Saunders, 1976.
STP, standard temperature and pressure.
The ability of modern oxygenators to mimic the capabilities of the native lung is remarkable, given the fundamental design differences between the two. In the native lung, red blood cells pass through pulmonary capillaries in single file, reducing the distance for O2 diffusion. Therefore, the rate of oxygen transfer is not limited by diffusion, except in the case of severe lung disease or extreme exercise (Table 1). Differences in gas tensions measured in the alveoli and in the pulmonary venous blood are mostly due to ventilation-perfusion mismatching. In an oxygenator, the distances are much greater, requiring features that gently mix blood at the membrane surface to increase gas transfer. Therefore, significant difference in partial pressures of gases exists between the gas and blood phases of oxygenators, even under normal operating conditions.
Oxygenators are mainly designed for short-term use on immobilized, anesthetized patients. Therefore, the total surface area for gas exchange is only a fraction (<5%) of the native lung. Oxygenators partially compensate for these limitations by increasing the blood path length (the distance that the blood travels past the gas exchange surface), thereby increasing the time available for blood exposure to the gas exchange surface, termed dwell time. Engineers also design oxygenators to create secondary flow, which disrupts laminar flow to promote mixing, bringing deoxygenated blood closer to the exchange surface (see Enhancing Gas Transport with Secondary Flows, in subsequent text).
Oxygenators can be ventilated with various percentages of O2 (21%-100%) by the use of a gas blender, blending medical grade air and oxygen, to maximize the driving pressure difference for O2 diffusion. Ventilation takes place through the flow of gas through the flowmeter, controlling the amount of carbon dioxide in blood like respiratory rate would on a ventilated native lung. However, even when ventilated with 100% O2, oxygenators cannot transfer the volume of gas native lungs are capable of; therefore they have very little reserve capacity (Table 1). Selection of devices for each clinical CPB procedure is P.49
based on an estimate of the metabolic demand of the patient, which is usually determined by the age of the patient, body size, and body composition. Adjunctive treatments such as anesthesia level, hypothermia, and muscle paralysis, all reduce the patient's metabolic requirements to the point where gas exchange requirements can ordinarily be met by one of these devices.
One of the most important recent advances in oxygenator design is minimizing the impact of extracorporeal circuit exposure to blood. Extracorporeal flow has been shown to induce proinflammatory mechanisms that exacerbate pathologic consequences, above that attributable to either the lesion or surgery. To reduce the CPB-induced systemic inflammatory response (SIR), oxygenators are available which have special coatings or treatments aimed at reducing the biochemical cascades affiliated with SIRs. It has been almost 20 years since the first large-scale commercial heparin-coated oxygenators became available (5). Since then, new generation coatings have been introduced with a similar goal of reducing the SIRs seen with CPB (6,7,8). Also, during the last few years there has been renewed interest in reducing the consequences of hemodilution, primarily to reduce anemia and dilutional coagulopathies. This has prompted clinicians and manufacturers to redesign the CPB circuit to minimize its imprint in an effort to create a “stealth” perfusion intervention (see Miniaturization or “Stealth” Perfusion Circuitry, in subsequent text). The remainder of this chapter will be devoted to examining the engineering challenges in the design of artificial lungs and the recent advances to make the extracorporeal surfaces less intrusive.
OXYGENATOR DESIGN
Bubble Oxygenators
When the first and second editions of this book were written, there were a fair number of heart centers that were utilizing the bubble oxygenator (bubbler) in clinical practice. However, engineering and production efficiencies for membrane oxygenators have vastly improved, which resulted in a reduction of manufacturing costs and an almost universal acceptance of their use. Although bubble oxygenator use has declined significantly over the last decade, there are centers that continue to use them for procedures that require only short periods of CPB. The simplicity of bubble oxygenator design, along with reduced manufacturing expense, promulgated the acceptance of CPB in hospitals throughout the world.
Structurally, a typical bubble oxygenator is divided into two sections (Fig. 7). Desaturated blood first enters passively (without active pressure) into a mixing chamber, where 100% oxygen flows across a disparager plate into the stream of blood, which causes small bubbles to form. The blood becomes oxygenated and carbon dioxide is reduced as the stream of gas percolates through the blood. A second session coalesces the bubbles, which then pass through a defoaming section where most of the gas separates from the blood. Blood is defoamed by the presence of silicone antifoam-A, which consists of the liquid polymer dimethylpolysiloxane (96%) and particulate silica (4%), which destabilizes the bubbles, causing them to implode. The arterialized blood is collected in an arterial reservoir that is then actively pumped from a collection reservoir into the patient.
The simple design of bubble oxygenators relied on a hydrostatic pressure head from the patient to the mixing chamber connected by the venous line to the right atrium or vena cava. Generally, the pressure drop through a bubble oxygenator is less than 30 cm of water, in contrast to the 100 cm of water pressure drop typically found in membrane oxygenators. Bubble oxygenators have the heat exchanger downstream from the bubble chamber but proximal to the blood pump so that heat exchange occurs simultaneous with gas exchange.
FLOW THROUGH AN OXYGENATOR
Blood flowing through oxygenators passes through two continuous or sequential compartments: the heat exchanger and the gas bundle. Blood flows first through the heat exchanger, which is separated from a temperatureregulated water source by either a metal or plastic heat exchanger, and then into the gas bundle (Fig. 1). The gas bundle makes up the core of the membrane oxygenator, and is most frequently made of microporous polypropylene fibers or less frequently a silicone sheet (Fig. 2). Gas moves into the liquid (blood) phase by diffusion, with the rate of movement determined by the partial pressure difference between the gas and fluid phases, and the diffusive characteristics of the solutions and materials. The diffusion is also affected by the gas composition and the concentration gradients of the particular gas. Other factors that affect gas transfer include the physical characteristics of the total surface area of the membrane module, and the physical design of the flow paths through the oxygenator.
Determinants of the PO2 and PCO2 in Gas and Blood
Dalton law describes how the partial pressure of gases present in a mixture of gases occupying a volume act as if each individual gas is occupying the volume act independently, with the sum of the individual gas partial pressures equaling the total gas pressure. This applies for gases occupying a space by themselves or dissolved in solutions such as blood. Therefore, when blood P.50
equilibrates at atmospheric pressure, the partial pressures or gas tensions of all gases dissolved in blood must add up to 760 mm Hg at sea level. In the gas phase, the partial pressure (P), the concentration (C), and the mole fraction are equivalent.
FIGURE 1. Fluid flow path through the heat exchanger portion of a Terumo RX15 oxygenator. Blood passes in the bottom of the heat exchanger and flows circumferentially around the stainless steel bellows in a countercurrent flow pattern. (Courtesy of Terumo Cardiovascular, Ann Arbor, MI.)
Unfortunately, CO2 and O2 content in blood do not derive solely from gases being dissolved in solution, complicating the analysis of gas transfer in oxygenators. The oxyhemoglobin dissociation curve shown in (Fig. 3) reflects the nonlinear binding of O2 by hemoglobin. The CO2 in the blood combines chemically with different moieties to form bicarbonate, the major carrier of CO2 in blood, and to amino groups of proteins, primarily hemoglobin, and is not linearly related to the partial pressure of CO2. Because of the chemical combination of CO2 and O2 to hemoglobin and the other moieties just described, both are present in much higher concentrations than would be possible simply by physical solution.
Gas Diffusion
Gas transfer in oxygenators occurs due to diffusion. Diffusion can be defined as the random motion of the atoms or molecules of the diffusing gas as they move from regions of higher concentration to regions of lower concentration. Fick law is used to describe the rate at which gases diffuse through gases, liquids, or solids. The rate of diffusion is proportional to the partial pressure gradient of the gas in the direction of diffusion (i.e., the difference of the partial pressure of the gas per unit distance). Therefore, the rate of diffusion per unit area, J, at a particular location, x, along the diffusion path would be described as:
FIGURE 2. Fluid flow path of through the gas bundle of the Sorin Biomedical Apex membrane oxygenator. Fluid enters the bottom of the oxygenator, moving upward, and across the membrane module. Outlet flow is at the base of the oxygenator. (Courtesy of Sorin Biomedical, Inc., Arvada, CO.)
where D is the diffusivity constant (a characteristic of the material and the gas) and P is the partial pressure of the gas at any particular location, x. The negative sign in the equation is the result of the negative value of the partial pressure difference, a result of the decreasing pressure in the direction of increasing distance, x.
Therefore, the rate of gas transfer can be increased by increasing the difference in partial pressure (represented by δP), increasing the surface area available for diffusion, P.51
and/or decreasing the distance through which the gas must diffuse (represented by δx). In the normal biologic lung, an increase in gas transfer occurs with an increase in the fraction of inspired oxygen concentration (FIO2) through an increase in δP. Alternatively, gas transfer would be decreased by edema through an increase in δx.
FIGURE 3. The oxygen hemoglobin dissociation curve. Use existing figure in second edition or this one taken from http://commons.wikimedia.org/wiki/Image:Hb_saturation_curve.png#file.
The diffusivity, D, is constant given a specific gas, barrier material, and temperature. Kinetic theory mandates that D is proportional to the molecular speed of the gas molecules, which, according to Graham law, is inversely proportional to the square root of the molecular weight of the gas. The D of a gas is also proportional to the solubility of the gas, complicating the analysis of gas transfer (9,10). Furthermore, gas diffusion in blood, particularly oxygen diffusion, is more complex than the description provided by Fick law. In addition to Fick diffusion through the plasma, the absorption of oxygen (or the release of carbon dioxide) occurs in red blood cells. Therefore, multiple diffusion gradients and multiple barriers to diffusion must be accounted for.
FIGURE 4. A: The laminar velocity boundary layer of fluid showing layers of fluid dragging each other along with greater velocity and momentum as the free stream velocity, Vs, is approached. The longer the line the faster the velocities with the shortest line having zero velocity at the wall interface. B: Turbulent velocity profile showing the effects of turbulence and the disruption of the boundary layer by the presence of protrusions at the wall of cylinder.
A second order differential equation can be derived that describes diffusion of oxygen in blood as a nonlinear function of distance and time, given the assumption that local differences in the partial pressures of O2 around the red cell are relatively minor compared with the overall O2 gradient. In the equation, time becomes an important factor in determining the rate of gas transport into the blood phase.
Momentum in a Flowing Fluid and Generation of the Stagnant Boundary Layer
A viscous fluid (such as blood) flowing through a fixed space will have variation in velocity, from a minimum of zero at the surface of the container, to that of the maximum velocity at the point most distal to the wall of the container. The regions where these variations occur are termed boundary layers. If the main stream of the fluid has a different velocity than the interface surface, a velocity gradient will be formed in which the fluid velocity varies from zero at the interface to Vs, the velocity in the main stream as shown in (Fig. 4A). This may be conceptualized as layers of fluid slipping or dragging over one another. Hence, as the distance from the wall increases, each subsequent layer has a greater velocity and momentum (momentum = product of mass times velocity). Therefore, momentum will vary from a maximum in the free stream to zero at the wall. As the flow continues along a surface, the boundary layer widens (known as the developing boundary layer). If the boundary layer widens to the point that it meets the growing boundary layer from the other side of the flow channel, then the flow is said to be fully developed.
The shape and contour of the velocity boundary layer(s) is important because it determines the overall resistance to flow or the pressure drop that occurs. At any place within the boundary layer the shear stress, τ, is proportional to the rate of change of velocity in the direction perpendicular P.52
to the main flow (the partial derivative of velocity, δu/δx) with the proportionality constant being the viscosity, µ, or
Therefore, an increase in the velocity gradient increases the shear stress.† The viscosity, µ, is constant for most fluids. Such fluids are referred to as newtonian fluids. However, some fluids, including blood, do not have a constant viscosity (i.e., the viscosity changes depending on the nature of the flow); these are called non-newtonian fluids. The primary determinant of blood viscosity is the concentration of red blood cells, which may vary between boundary layers. At the wall, the shear stress, τw, is also related to the steepness of this velocity gradient. The integral or summation of all the wall shear stresses over the entire wall surface area is what determines the pressure drop of any viscous flow.
Velocity profiles will also vary by the tendency of the flow stream to produce either laminar or turbulent flow. Turbulent flow generates spontaneous eddies from flow instabilities within the flow. Such a flow would have a high Reynolds‡ number (a nondimensional number used to predict the transition from laminar to turbulent flow). Turbulence can also result from an irregularity in the flow path, creating eddies within the flow (see Enhancing Gas Transport with Secondary Flows in subsequent text). Figure 4B shows how turbulence can change the boundary layer velocity profile by moving higher velocity fluid into the boundary layer closer to the surface, causing a steeper rise in the velocity profile (shear rate) and in shear stress.
As a fluid flows past a surface through which gas diffusion is occurring, a diffusion boundary layer is generated that mirrors the velocity boundary. The diffusion boundaries still depends on Fick law, but the variables within are different for each layer. For oxygen diffusion of a standard membrane lung, the oxygen partial pressure in the fluid varies from Pw, the partial pressure of oxygen at the interface with the blood, to Ps, the partial pressure within the stream not yet affected by the diffusion of gas to or from the wall. Note that in (Fig. 5) the O2 partial pressure decreases slightly in the membrane itself but rapidly decreases in the blood. This graphically represents the actual physical condition. In membrane oxygenators, the largest resistance to O2 diffusion occurs within the blood itself due to the low D of O2 in blood. As the bloodstream flows along the interface, the boundary layer of O2 grows in a manner similar to that described for the velocity boundary layer. As the width of this boundary layer increases, the diffusion distance increases and hence the rate of gas diffusion decreases because of the greater diffusion distance. The time allotted for gas diffusion also varies due to variation in the velocity of the blood with the boundary layers.
FIGURE 5. Typical variation of oxygen partial pressure from the membrane of an artificial lung to the free stream of blood.
†Note that shear stress, τ, is a force applied to a unit area and thus has units of pressure. The force, however, is applied tangentially to or across the area, unlike pressure, in which the force is applied perpendicular to the area. Furthermore, note that the velocity gradient, δu/δx, is usually referred to as the shear rate.
‡The Reynolds number is defined as the ratio of inertial to viscous forces, or Re = p • U • d/µ (p = density, U = velocity, d = chamber diameter, µ = viscosity).
Principles of Heat Transfer
Heat transfer is the transfer of kinetic energy from molecules with higher energy (higher temperature) to molecules with lower energy (lower temperature). In practice, heat transfer can occur in one of three ways: conduction (from solid to solids), convection (from solids to liquids), and radiation (an electromagnetic mechanism). Within the CPB heat exchanger, the primary form of heat transfer is forced convection (the water and blood of the heat exchanger are actively pumped past the stainless steel interface, hence the term forced), with conduction occurring within the stainless steel.
The flow of energy or heat, Q, is proportional to the temperature difference by the thermal conductivity, K, a constitutive property of any material, such that
where T is the temperature at any point and x is the distance. This equation is the one-dimensional form of Fourier law of heat conduction. In a manner similar to gas transfer, boundary layers are created as blood flows past the heat exchanger surface. Therefore, a thermal boundary layer is generated in which the temperature varies from the temperature of the wall to that of the free stream yet unaffected by the heat exchanger.
P.53
TABLE 2 Comparison of Momentum Transfer, Heat Transfer, and Mass Transfer (Diffusion)
Transfer
Driving Force Flow
Defining Equationa
Momentum
Velocity gradient
Momentum τ = -µδu/δx
Heat
Temperature gradient Heat (energy)
Q= -KδT/δx
Mass (diffusion)
Concentration gradient
Mass (diffusing gas) J=-DδP/δx
a The negative signs in these equations are the result of standard conventions used in defining positive and negative directions. See text for explanation of equations.
Analogs of Momentum, Mass, and Heat Transfer
Marked similarity exists between the movement of momentum in the velocity boundary layer, gas diffusion, and heat transfer in the heat exchanger (Table 2). The most striking feature is the resemblance of the defining equations, as shown in the right column. Although these equations are simpler than the actual equations needed to describe the physical situations, they provide insight into the nature of the equations.
Enhancing Gas Exchange with Secondary Flows
As noted, the primary resistance to gas diffusion occurs in the blood phase (11). Efforts to improve gas exchange have focused on reducing this diffusion barrier (12,13). A primary method for enhancing gas diffusion would be increasing the driving gradient (limited to 760 mm Hg—oxygen tension in blood). The ability to increase the diffusion gradient by increase the gas phase oxygen tension (increasing FIO2) is typically held available as a reserve capacity. Instead, increasing dwell time or decreasing the diffusion path is used to improve gas exchange at the time of design. Increasing the dwell time will also increase surface area and priming volume. Therefore, decreasing the diffusion path has been targeted to enhance gas transfer. First, the blood path thickness has been minimized as much as technically feasible by placing the membranes as close together as possible without causing an excessive pressure drop across the oxygenator. The major advance has been the utilization of induced eddies or secondary flows of the blood (14) from the primary stream into the diffusion boundary layer, thereby decreasing the thickness of this layer and increasing the gas transfer.
Unfortunately, the movement of blood into the diffusion boundary layer impacts the blood velocity of the boundary layer, increasing the shear stresses within the boundary layer and at the wall. The result is an increase in shear stress within the boundary layer, leading to increased damage to the formed elements of blood. In addition, increasing wall shear stresses increases the blood pressure drop across the oxygenator. As such, the need for maximal gas transfer capability must be balanced against the potential for damaging the blood.
MEMBRANE OXYGENATORS
Membrane Types
A variety of membrane materials have been used for gas transfer and have included cellophane, nylon, polyethylene, ethyl cellulose, Teflon, butyl rubber, silicon, polypropylene, and polymethyl pentene. However, the membrane materials that have been found to provide the best gas transfer characteristics with minimal cellular trauma have been silicone and polypropylene, and have become the standard materials used for oxygenators currently.
In 1963, Kolobow and Bowman described the development of a membrane made out of silicone polymer material wound in a coil that they described as an alveolar membrane artificial lung (15). The silicone barrier separated the gas and blood phases so that gas transfer was totally dependent upon the diffusion of gas through the membrane material. This was termed a true membrane, as opposed to oxygenators made of materials with microscopic pores throughout the membrane material. The silicone polymer is a bioinert material that provided improved biocompatibility, enhancing its utility for long-term support. Silicone membranes were used in clinical CPB procedures from the 1980s through the mid-1990s but fell out of favor for routine CPB procedures due to difficulties in manufacturing and quality control. They also had gas exchange characteristics that were inferior to that of polypropylene materials, requiring greater surface areas and larger prime volumes. Owing to compatibility issues, silicone membranes continue to be the membrane of choice for long-term procedures such as ECLS/ECMO.
New generation membranes have been developed that incorporate the benefits of silicone with polypropylene (16,17). The silicone membrane has been shown to be superior to the microporous membrane lung for long-term support without a diminution in gas transfer capacity. One of the major problems with using microporous membrane materials for periods greater than 24 hours is their propensity to develop plasma leakage and membrane wet-out (18,19,20). Wetting of the membrane module is termed plasma leakage and occurs when blood plasma slowly fills the pores of the fiber wall and leaks into gas pathways, increasing the diffusion distance and decreasing gas exchange (21,22). Silicone membranes avoid plasma leakage. The Kolobow oxygenator (Fig. 6) uses a continuous sheet of silicone membrane rolled into a coil. Oxygenators of this style are manufactured by P.54
Medtronic Cardiopulmonary, Inc. (Minneapolis, MN) and are available in membrane surface area sizes from 0.6 to 4.5 m2. The available sizes readily accommodate the most common use of this device, ECLS/ECMO in neonates, pediatrics, and adults.
FIGURE 6. Scanning electron micrograph of hollow fibers from an Apex membrane oxygenator. (Courtesy of Sorin Biomedical, Inc., Arvada, CO.)
Microporous polypropylene membrane oxygenators are the predominant design used for CPB in the world currently. There are two major types or configurations of the membrane material—hollow fiber designs and folded sheets with hollow fibers making up the predominance of devices (Fig. 7). The polypropylene comes from a variety of manufacturers but is relatively consistent in its size and dimensions (Fig. 6). The micropores making up the membrane material are created by a process of extrusion, where the membrane material is stretched and then heated creating microchannels (23,24). These microchannels are pores less than 1 µm in diameter, although the size varies among manufacturers. The membrane is initially porous, before being exposed to proteins in plasma, which allows at least a transient direct blood-gas interfacing at the initiation of CPB. After a short time, protein coating of the membrane and gas interface takes place, and no further direct blood and gas contact exists. The surface tension of the blood prevents plasma water from entering the gas phase of the micropores during CPB. Likewise, surface tension of the blood prevents gas leakage into the blood phase, which would create gaseous microemboli and denature the blood proteins. The surface tension of the blood at the micropores can be overcome if the gas compartment pressures are allowed to the exceed blood compartment pressure, raising the risk of gas emboli. The micropores provide conduits through the polypropylene membrane that give sufficient diffusion capability to the membrane for both oxygen and carbon dioxide exchange. After several hours of use, however, the functional capacity of micropore membrane oxygenators decreases because of evaporation and subsequent condensation of serum that leaks through the micropores.
FIGURE 7. Microporous hollow fibers used in the construction of a membrane oxygenator. A: Unbundled hollow fibers demonstrating cylindrical shape. B: Wound mat of hollow fibers used in membrane bundle of the Terumo SX oxygenator line. (Courtesy of Terumo Cardiovascular, Inc., Ann Arbor, MI.)
Membrane Configuration and the Creation of Gas and Blood Flow Pathways
In the hollow fiber design, blood flow is around the fiber bundle while gas flows through the hollow fibers, which have a cylindrical shape similar to that seen in straws. P.55
The manufacture of the membrane module of a hollow fiber oxygenator occurs by wrapping hollow fibers around a central mandrel in a precise and reproducible manner, assuring consistency in fiber bundle geometry. The ends of the fiber bundle are then dipped in a vat of polyurethane and allowed to dry, creating a seal at each end of the bundle. A high-speed saw is then used to make precise slices at right angles to the fiber bundle, creating sealed ends on each side of the membrane module with only the fibers open to atmosphere. These ends then become the gas inlet and outlet sections of the membrane bundle (Fig. 8).
Historically there were two options for blood flow through a hollow fiber oxygenator: through the fiber or around it. The former was abandoned due to high transmembrane pressure, the activation of platelets, and the increased hemolysis (25). Blood may flow either perpendicular to the fiber bundle (crosscurrent) or in the direction of the fibers (Fig. 9). In the latter case, blood will flow in a countercurrent direction to the gas flow, which confers the advantage of optimized gas gradients during the dwell time.
An important engineering consideration with the design of membrane bundles is the reduction of streamlining, which is the flow of blood through an oxygenator without gas exchange. Streamlining is an example of an extracorporeal ventilation perfusion mismatch reducing oxygenator performance. The application of sophisticated engineering programs to design and evaluate models of thermofluid phenomena has removed much of the trial and error of oxygenator design (26). Computational fluid dynamics (CFD) is a numerical approximation of the nonlinear partial differential equations, which govern fluid flow. The resulting CFD designs provide a visual depiction of membrane flow dynamics and pressure drops and identify areas of high blood shear and stasis, both of which lead to inefficient function and activation of formed elements of blood. CFD has become an industry standard and is used by all manufactures in the design of oxygenators and other extracorporeal equipment (Fig. 10).
FIGURE 8. Top section view through a synthesis polypropylene membrane oxygenator. Venous blood enters the center of the device and flows across the heat exchanger and then through the membrane material, before exiting the polycarbonate housing. (Courtesy of Sorin Biomedical, Inc., Arvada, CO.)
FIGURE 9. Computational fluid dynamics illustration of flow pattern traversing an oxygenator bundle. Changing color indicates a change in velocity of fluid movement and an increase in shear rate. (Courtesy of Sorin Biomedical, Inc., Arvada, CO.)
FIGURE 10. Membrane oxygenator with fluid flow through central core and at right angle across fiber bundle. Affinity membrane oxygenator. (Courtesy of Medtronic Cardiopulmonary, Inc., Minneapolis MN.)
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Operation and Control of Membrane Oxygenators
The control of ventilation and oxygenation is relatively independent in membrane oxygenators. Increasing the total gas flow, or sweep rate, increases CO2 elimination by reducing the gas phase CO2 partial pressures and likely decreasing the gas phase boundary layers. Gas flow is regulated by the use of the flowmeter with a gas mixture of medical grade air (a mixture of oxygen and nitrogen gases) and oxygen through the gas blender. Blood oxygenation is controlled by manipulating the FIO2 in the gas blender. Fortunately, the membrane oxygenator separates the blood and gas phases and does not introduce gas bubbles into the blood, so the addition of nitrogen to the gas flows does not increase the risk of gas emboli. The mixture of gases allows for the precise control of ventilating gas, allowing the perfusionist to adjust the partial pressure of oxygen in the arterial blood leaving the oxygenator. Although controversy exists regarding the appropriate partial pressures to maintain during CPB, it is generally accepted that a PaO2 in the range of 150 to 250 mm Hg and PaCO2 of 35 to 45 mm Hg is effective to assure adequate acid-base status in most patients (27).
QUANTIFICATION OF OXYGENATOR PERFORMANCE
Measurement of Gas Transfer
The use of in-line blood gas monitors during CPB is growing more popular (3,4,27,28). These devices allow a continuous measurement of PaO2, PaCO2, pH and temperature as well as hematocrit, hemoglobin, and the saturation of hemoglobin in venous blood (SvO2). The benefit of having continuous monitoring of this information is clinically relevant, because the use of standard oximetry is precluded by nonpulsatile flow. A second useful aspect of in-line monitoring can arise if the determination of gas exchange becomes is critical (29). In the case of oxygenator dysfunction, it is critical to distinguish between oxygenator dysfunction and a more frequently encountered hypermetabolic condition (1). In the blood phase, gas transfer can be calculated by application of conservation of mass (Fick principle) as shown in Eq. 4. The determination of oxygenator function is made by calculating the oxygen consumption of the patient and comparing this to the known gas transfer capacity of the oxygenator. If the calculated amount is within the range of predicted oxygen or carbon dioxide transfer, then the oxygenator is performing according to specifications and the patient is in a hypermetabolic state or an inappropriate oxygenator was selected. However, if the gas transfer is less than the predicted value, then the oxygenator may be malfunctioning and may need to be changed with a second device.
VO2 is the oxygen transport, Q is the blood flow rate, and C is the oxygen content, with a and v representing the arterial and venous values, respectively.
Gas transfer can also be determined in the gas phase of the oxygenator concurrently with that of the blood phase measurements. Mass spectrometers are found in most anesthesia machines, which can be used to measure the gas concentrations of the gas flowing into and out of the oxygenator. The difference of O2 in inlet and outlet gas concentrations can then be multiplied by the total gas flow rate to determine the O2 transfer rate:
In this case, Q is the gas flow rate and FIO2 and FEO2 are inlet and outlet gas oxygen fractions, respectively.
Industrial Standardization of Gas Transfer and Blood Flows
To compare oxygenator capabilities, standards have to be created for the determination of oxygenator function. The Association for the Advancement of Medical Instrumentation (AAMI; Arlington, VA) developed and reviewed oxygenator standards. Reliance on AAMI standards has come under question because the variability in gas transfer values is dependent on the starting range of inlet conditions. Fried et al. have questioned this variability and have shown that improvements in gas transfer of individual devices can be achieved by manipulating the experimental conditions by which the oxygenators are evaluated (30,31), which was confirmed in an editorial by Ueyama et al. (32).
TERMS AND DEFINITIONS
Carbon Dioxide Reference Blood Flow
This is the flow rate of normothermic whole blood having a hemoglobin content of 12 g/dL, zero base excess, and venous oxygen saturation of 65% that has its carbon dioxide content decreased by 38 mL CO2 (standard pressure and temperature) per L of blood flow by direct passage through the oxygenator.
Oxygen Reference Blood Flow
This is the flow rate of normothermic whole blood having a hemoglobin content of 12 g/dL, zero base excess, and venous oxygen saturation of 65% that has its oxygen content increased by 45 mL O2 (standard pressure and temperature) per L of blood flow by passage through the oxygenator.
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Reference Blood Flow
This is the lowest of the following: oxygen reference blood flow, carbon dioxide reference blood flow, the manufacturer's recommended blood flow, or a blood flow of 8 L/min.
Index of Hemolysis
Quantity (in milligrams) of plasma-hemoglobin generated in the in vitro cellular damage test per 100 L of blood pumped through the circuit containing the oxygenator less the quantity generated in the circuit without the oxygenator.
Initial Priming Volume
This is the volume of blood (in milliliters) to fill the blood phase of the device, including the heat exchanger, to the manufacturer's recommended minimal reservoir level.
Maximum Operating Volume
Volume of blood contained in the device at the maximum reservoir level recommended by the manufacturer at reference blood flow and reference oxygen flow.
Minimum Operating Volume
The minimum volume contained in the venous reservoir recommended by the manufacturer at the reference blood flow and reference oxygen flow.
HEAT TRANSFER DURING CARDIOPULMONARY BYPASS
Heat Exchangers
Heat exchangers are integral components of all oxygenators used for CPB and can be external in oxygenators used for ECLS/ECMO. Heat exchangers function in combination with an external heater-cooler or with wall sources of water, that pump temperature-controlled water into the water phase of the heat exchanger, which is separated from the blood phase by a highly conductive material. The function of the heat exchanger is to regulate the temperature of the blood perfusing the patient, which then raises or lowers the body temperature depending on the type of surgical procedure being performed. Heat exchangers must be made of biologically inert materials that reduce the risk for excessive activation of cellular and noncellular elements of blood.
The transfer of energy occurs by the circulation of water from the heater-cooler unit, which is part of the CPB equipment. When cooling is desired, the water temperature is reduced by activating a chilling unit within the device. Older style heater-coolers had a large reservoir to which ice could be added to reduce water temperature. Likewise, warming of the water in the heater-cooler is a function of high-wattage resistance units within the device. New generation models have digital regulating modules that allow the precise control of temperature through thermostat-controlled heating and cooling elements within the console. Other techniques for maintaining or controlling patient temperature during a surgical procedure include the use of warming or cooling blankets placed below the patient, and ambient control of room temperature.
The heat transfer surface is usually made of stainless steel, aluminum, or polypropylene. The material used should have good thermal conductivity and are coated with polymers or other surface-modifying agents to minimize blood activation. To maximize heat efficiency of heat transfer, blood and water pathways flow in a counter current direction, which also reduces outgassing of solutions due to rapid changes in temperature. Although increasing heat exchanger surface area results in a greater heat transfer, it requires larger prime volume and more severe hemodilution.
Constraints on Rate of Heat Transfer
The temperature difference between the circulating water from the heater-cooler and the blood determines heat transfer. A thermal boundary layer exists in the blood flowing just beside the wall of the heat exchanger (i.e., the wall separating blood and water), an area where the temperature varies from the wall temperature to the free stream temperature (33). The exact temperature profile in the boundary layer depends on the nature of the velocity of fluid movement, but a typical profile would appear similar to the curves shown earlier for gas concentrations during diffusion (Fig. 4A,B).
Changing temperature alters the solubility of gases within the solution, and higher partial pressures of gas increase the rate of outgassing of the solution. It is well appreciated that warming of a solution will increase intrinsic kinetic energy which results in higher molecular collisions, leading to outgassing. Due to the potential for gas emboli from outgassing, historic reports suggested the maintenance of a maximum of a 10°C temperature difference between the waterside of a heat exchanger and the blood side. However, recent work has questioned the safety of a 10°C gradient. Grigore et al. have recommended using reduced temperature gradients (<6°C) and longer rewarming times to improve neurocognitive outcomes in patients undergoing coronary artery bypass graft surgery with CPB (34). In addition, the induction of a hyperthermia circulatory temperature to rewarm peripheral vascular beds has resulted in central P.58
nervous system dysfunction (35,36). Blood damage, in the form of protein denaturation, limits the absolute maximum temperature (42°C) that can be safely achieved in the blood (37).
Determination of Rate of Heat Transfer
The amount of heat being transferred is readily quantifiable (38,39) by simple energy balance, as defined by the first law of thermodynamics. This relation requires that the amount of heat transferred to the blood equals the thermal energy in the blood leaving the oxygenator less the thermal energy of the blood entering the heat exchanger. The thermal energy of blood can be determined by multiplication of the specific heat of blood, C (0.90 kcal/kg/°C) (40) by the absolute temperature. Therefore, the heat transfer can be calculated by
where C is the specific heat, F is blood flow rate, and Ti and To are the inlet and outlet temperatures, respectively. This provides the instantaneous heat transfer (heat/unit time usually expressed in kcal/min). If this quantity is then integrated either continuously or in a finite manner over discrete time intervals, the total amount of heat transferred into or from the patient can be determined. The use of this method may provide an alternative method of assessing the adequacy of rewarming during CPB in the future.
OXYGENATOR TREATMENTS
Oxygenator Coatings
The oxygenator, composed of several different types of synthetic materials, represents the largest surface area within the extracorporeal circuit. The nonendothelialized surfaces of the circuit elicit an SIR (41), and the oxygenator is a primary target for surface modifications aimed at improving biocompatibility. Biocompatibility, defined as the ability of biomaterials to perform without a host response, is usually expressed by the levels of bioactive substances present in the circulation after contact with the biomaterials. Surface modification of extracorporeal circuits has been studied for more than 40 years with the initial goal to reduce the thrombogenic quality of synthetic surfaces (42). In the early 1980s several cardiopulmonary device manufacturers began heparin coating common perfusion supplies including the oxygenator (Duraflo II, Edwards LifeSciences, Irvine, CA, Carmeda Bioactive Surfaces, Medtronic Inc., Minneapolis, MN). Despite evidence supporting an anti-inflammatory benefit of their use (43,44,45,46), acceptance of these coatings in routine clinical practice was low, with utilization in the United States reported at approximately 17% of all perfusions (1). New generation coating and/or surface modifications that do not utilize heparin seek to overcome the limitations of early generation materials.
All the major manufacturers of cardiovascular perfusion equipment have either developed, or are in the process of developing, modifications of the surfaces of circuitry used for CPB.§ Results of most studies examining coated circuitry demonstrate an overall reduction in the inflammatory markers elevated as a result of CPB. Unfortunately, the significance of showing improved biocompatibility through reduced biological markers has not equivocally correlated to measurable clinical benefit of surface modification during CPB (47,48,49). It is for this reason, and the increased cost associated with their use, that the incorporation of coated circuitry has not been accepted more broadly in perfusion. However, many of these studies were performed on isolated surgical coronary revascularization patients and the results may not transfer to a more complex patient population undergoing combined procedures (50,51).
§Surface Modifying Additive—polydimethylsiloxane polycaprolactone oligomer, Sorin Biomedical, Arvada, CO; Phosphorylcholine—Dideco, Mirandola, Italy; Bioline—Jostra AG, Hirrlingen, Germany; X Coating—poly(2-methoxyethylacrylate, Terumo Cardiovascular, Ann Arbor, MI; Trillium Biopassive Surface—polyethylene oxide, Medtronic Cardiopulmonary, Minneapolis, MN.
Collection and Sequestration of Aspirated Blood from Extracorporeal Circuit
A recent effort to reduce the SIR effect of extracorporeal circulation has been the cessation of collecting aspirated blood into the extracorporeal circuit during CPB. Aldea et al. have described a multifactorial approach to ameliorating the effects of extracorporeal circulation on patient outcomes (52,53). The process of aspirating shed blood from pericardial and mediastinal areas results in an accumulation of highly activated cellular elements of blood and their activated mediators (54). Reinfusion of this aspirate has been shown to exacerbate the inflammatory response above that caused by CPB itself, which led to the suggestion that the blood be discarded or processed by the use of a centrifugal cell-washing device (55,56,57,58,59). However, the removal of this blood will result in a decreased red cell volume, potentially lowering the hematocrit and increasing the risk of allogeneic transfusion. Likewise, processing of this blood with a cell-washer device removes plasma proteins and platelets, potentially increasing the risk of bleeding, transfusion, and edema.
To address the issue of shed blood, one manufacturer designed an oxygenator with a separate cardiotomy reservoir contained within the venous reservoir (Avant, P.59
Dideco Biomedical, Mirandola, Italy). The device can isolate the collected pericardial and mediastinal blood from the venous reservoir in a cardiotomy reservoir that has a nonsequential flow pattern as is typical in hard-shell venous reservoirs (Fig. 11). The sequestered blood can either be transferred to a cell-washing device or reinfused into the venous reservoir if volume is required to maintain adequate perfusion. Although data supporting the benefit of sequestration is scarce, one report has shown a significant transient reduction in plasma-free hemoglobin levels during CPB (60).
FIGURE 11. Avant Dideco D903 membrane oxygenator with dual chamber reservoir. (Courtesy of Sorin Biomedical, Inc., Arvada, CO.)
Miniaturization or “Stealth” Perfusion Circuitry
One of the emerging trends in CPB has been an effort to reduce the impact that the extracorporeal circuit has on the morbidity associated with cardiac surgery. As has been discussed, the modification of circuit surfaces by coatings and treatments to reduce the SIR has not been enthusiastically accepted. However, efforts to reduce circuit prime volumes and further reduce hemodilution are generally embraced. The reduction in hemodilution should lower both anemia and transfusion risk. The design of traditional CPB circuitry has been as an open system where venous blood is collected in a large volume “holding” reservoir from which it is pumped through the oxygenator and into the patient. Safe CPB has traditionally used terms such as pump volume and reaction time, both of which are reflections of safe operating levels for the conduct of perfusion. Concomitant aspects of this safety function has been increased circuit surface areas, presence of bioreactive substances like defoaming agents within the venous reservoir, and induced hemodilution to maintain reservoir levels. Closed systems for CPB would instead use the patient's vascular system as the venous reservoir and use assisted venous return as a means to achieve drainage, and hence, adequate flow. This type of CPB has been termed mini-bypass or more appropriately stealth perfusion.
One of the earliest commercial attempts to miniaturize bypass circuitry was the development of an integrated pump oxygenator as a single perfusion system without accessory pumps for aspiration and venting (CORx System, CardioVention, Inc., Santa Clara, CA). The system had an integrated pump oxygenator that used a centrifugal pump to kinetically drain venous blood from the patient. There was an air evacuation system for the removal of air from the venous line that was entrained around purse string sutures or during the inadvertent opening of the right atrium or cava to atmosphere. Temperature was controlled by an optional heat exchanger that could be placed in the arterial line leading to the patient. All shed blood, vented blood, and blood removed during air evacuation was discarded or sent to a cell-washing system. The primary benefit of the system was a reduced prime volume, as low as 500 mL, and reduced surface area with an oxygenator bundle of 1.1 m2. An ultrasonic device detected air in the venous line proximal to the centrifugal pump, which activated the air evacuation system that aspirated air to a collection reservoir. Several authors evaluated this device and found a significant reduction in prime volume when compared with conventional CPB systems and lower release of inflammatory mediators (61,62,63). However, there were a number of problems that quickly became apparent when closed perfusion systems were utilized. These included reduced margins of safety in handling volume loss, increased blood loss, and increased potential for air embolism (64). Perhaps most challenging, significant modification in the conduct of CPB was required when using a kinetically assisted closed system. For these reasons the CORx System did not gain support and is no longer manufactured. However, the principles of stealth perfusion are gaining momentum, and several cardiopulmonary companies have developed miniaturized CPB systems: Minimal Extracorporeal Circulation System (MECC)—Jostra AG, Hirrlingen, Germany; Performer Medtronic Cardiopulmonary, Minneapolis, MN; Synergy—Sorin Biomedical, Arvada, CO). Both the Medtronic and Jostra systems utilize traditional extracorporeal components that have been modified to perform closed system CPB. However, the Sorin Synergy utilizes a unique oxygenator design that incorporates a centrifugal pump, oxygenator, and arterial line filter (Fig. 12).
Stealth perfusion techniques will likely continue to develop and expand. The changes in cardiac surgery patients (i.e., increasing preoperative risk, increasingly P.60
complex operative requirements) and changes in the demand for CPB have collided with an increased knowledge base and an expanded appreciation for the physiology of CPB. These elements compliment the need for improving the conduct of CPB. Stealth perfusion—including reducing allogeneic transfusions and anemia through improved perfusion techniques and technology, concurrent with surface modification and decreased surface area to reduce the SIR—should continue to be embraced.
FIGURE 12. The Sorin Biomedical Synergy integrated membrane oxygenator—centrifugal pump—arterial line filter. (Courtesy of Sorin Biomedical, Inc., Arvada, CO.)
KEY POINTS
The ideal artificial lung (oxygenator) transfers oxygen into and carbon dioxide out of the body at physiologic blood flow rates with minimal blood trauma and a small priming volume.
Compared with natural lungs, artificial lungs have much smaller surface areas and are limited by diffusion, thereby having limited reserve for gas transfer. Despite improved oxygenator designs, the maximum oxygen transfer of artificial lungs is less than 25% that of normal lungs.
Gas transfer across an oxygenator is proportional to partial pressure difference and surface area and inversely proportional to diffusion distance.
At the interface between gas and blood with laminar flow characteristics the velocity of blood flow incrementally increases from zero at the interface of the wall to free stream velocity at a distance most distal from the interface. This velocity transition zone is termed the boundary layer, and gas diffusion is inversely proportional to its thickness. The thickness of this boundary layer, and thereby the efficiency of the oxygenator, can be improved by creating secondary “eddy current” flows at this interface.
Direct contact oxygenators (such as disk or bubble devices) place bubbles in direct contact with the blood, causing increased cellular trauma as compared to membrane type devices.
Most membrane oxygenators use microporous membrane materials, although some devices use a silicone medium and are termed true membranes. True membranes offer advantages in longer perfusions (days to weeks), because microporous membrane lungs eventually develop leaks that produce “oxygenator pulmonary edema.”
Important aspects of microporous membrane lungs include (a) absence of a direct blood-gas interface once the membrane develops a proteinaceous coating; (b) relatively high resistance to flow, such that blood must be actively pumped across the device; and (c) independent regulation of PaCO2 and PaO2 by varying ventilating gas flow (PaCO2) and FIO2 (PaO2).
Standards have been developed for assessing oxygenator CO2 and O2 transport capacities, hemolysis indexes, priming volumes, and maximum and minimum operating volumes. Reference blood flow is defined as the lowest of the oxygen reference blood flow, carbon dioxide reference blood flow, manufacturer's reference blood flow, or a blood flow of 7 L/min.
Heat exchangers are integrated into oxygenators to permit cooling and warming of the bloodstream by the use of an external heater-cooler, which varies the water temperature flowing into the heat exchanger. The exchange surfaces are typically made of stainless steel, aluminum, or polypropylene and have protrusions to maximize the efficiency by disrupting boundary layer conditions.
To prevent formation of gaseous microemboli, the temperature gradient between water and blood should not exceed 6°C.
New generation artificial lungs integrate multiple components, such as arterial line filters and/or centrifugal pumps, into the oxygenator.
Future development in oxygenators and related devices use a “stealth” approach to reducing the imprint of extracorporeal systems on patient response.
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41. Elahi MM, Khan JS, Matata BM. Deleterious effects of cardiopulmonary bypass in coronary artery surgery and scientific interpretation of off-pump's logic. Acute Card Care 2006;8:196-209.
42. Gott VL, Whiffen JD, Datton RC. Heparin surface bonding on colloidal graphite surface. Science 1963;142:1297-1298.
43. Mahoney CB. Heparin-bonded circuits: clinical outcomes and costs. Perfusion 1998;13:192-204.
44. Stammers AH, Christensen KA, Lynch J, et al. Quantitative evaluation of heparin coated versus non heparin coated bypass circuits during cardiopulmonary bypass. J Extra Corpor Technol 1999;31:135-141.
45. Jansen PGM, te Velthuis H, Huybregts RAJM, et al. Reduced complement activation and improved postoperative performance after cardiopulmonary bypass with heparin coated circuits. J Thorac Cardiovasc Surg 1995;110:829-834.
46. Zimmermann AK, Weber N, Aebert H, et al. Effect of biopassive and bioactive surface-coatings on the hemocompatibility of membrane oxygenators. J Biomed Mater Res B Appl Biomater 2007;80:433-439.
47. Gorman RC, Ziats N, Rao AK, et al. Surface-bound heparin fails to reduce thrombin formation during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996;111:1-11.
48. van den Goor JM, van Oeveren W, Rutten PM, et al. Adhesion of thrombotic components to the surface of a clinically used oxygenator is not affected by Trillium coating. Perfusion 2006;21:165-172.
49. Ereth MH, Nuttall GA, Clarke SH Jr, et al. Biocompatibility of trillium biopassive surface-coated oxygenator versus uncoated oxygenator during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2001;15:545-550.
50. Goudeau JJ, Clermont G, Guillery O, et al. In high-risk patients, combination of antiinflammatory procedures during cardiopulmonary bypass can reduce incidences of inflammation and oxidative stress. J Cardiovasc Pharmacol 2007;49:39-45.
51. Trowbridge CC, Stammers AH, Wood GC, et al. Improved outcomes during cardiac surgery: a multifactorial enhancement of cardiopulmonary bypass techniques. J Extra Corpor Technol 2005;37:165-172.
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52. Aldea GS, Soltow LO, Chandler WL, et al. Limitation of thrombin generation, platelet activation, and inflammation by elimination of cardiotomy suction in patients undergoing coronary artery bypass grafting treated with heparin-bonded circuits. J Thorac Cardiovasc Surg 2002;123:742-755.
53. Lilly KJ, O'Gara PJ, Treanor PR, et al. Heparin-bonded circuits without a cardiotomy: a description of a minimally invasive technique of cardiopulmonary bypass. Perfusion 2002;17:95-97.
54. Pierce ML, Stammers AH, Dickes MS, et al. Is fibrinolytic activity stimulated during cardiopulmonary bypass from blood exposed to pleural surfaces? J Extra Corpor Technol 1998;30:120-126.
55. De Somer F, Van Belleghem Y, Caes F, et al. Tissue factor as the main activator of the coagulation system during cardiopulmonary bypass. J Thorac Cardiovasc Surg 2002;123:951-958.
56. Carrier M, Denault A, Lavoie J, et al. Randomized controlled trial of pericardial blood processing with a cell-saving device on neurologic markers in elderly patients undergoing coronary artery bypass graft surgery. Ann Thorac Surg 2006;82:51-55.
57. Westerberg M, Bengtsson A, Jeppsson A. Coronary surgery without cardiotomy suction and autotransfusion reduces the postoperative systemic inflammatory response. Ann Thorac Surg 2004;78:54-59.
58. Skrabal CA, Khosravi A, Choi YH, et al. Pericardial suction blood separation attenuates inflammatory response and hemolysis after cardiopulmonary bypass. Scand Cardiovasc J 2006;40:219-223.
59. Westerberg M, Gabel J, Bengtsson A, et al. Hemodynamic effects of cardiotomy suction blood. J Thorac Cardiovasc Surg 2006;131:1352-1357.
60. Pierangeli A, Masieri V, Bruzzi F, et al. Haemolysis during cardiopulmonary bypass: how to reduce the free haemoglobin by managing the suctioned blood separately. Perfusion 2001;16:519-524.
61. Abdel-Rahman U, Martens S, Risteski P, et al. The use of minimized extracorporeal circulation system has a beneficial effect on hemostasis-a randomized clinical study. Heart Surg Forum 2006;9:E543-E548.
62. Abdel-Rahman U, Ozaslan F, Risteski PS, et al. Initial experience with a minimized extracorporeal bypass system: is there a clinical benefit? Ann Thorac Surg 2005;80:238-243.
63. Bein B, Caliebe D, Scholz J, et al. A new cardiopulmonary bypass circuit with reduced foreign surface (CorX): initial clinical experience and implications for anaesthesia management. Eur J Anaesthesiol 2004;21:982-984.
64. Nollert G, Schwabenland I, Maktav D, et al. Miniaturized cardiopulmonary bypass in coronary artery bypass surgery: marginal impact on inflammation and coagulation but loss of safety margins. Ann Thorac Surg 2005;80:2326-2332.
The US Food and Drug Administration (FDA) have outlined key areas of importance pertaining to arterial line filters (FDA, 2000). These are summarized as follows: amount of damage to formed blood elements, for example, clotting and hemolysis; degree of pressure drop resulting in inadequate blood flow, damage to the device, structural integrity and damage to the arterial line; structural integrity of the product; excessive pressure gradients, for example, blood damage and inadequate blood flow; filtration efficiency and gas emboli-handling capacities; user error; blood incompatibility and the requirements of ISO 10993: Biological Evaluation of Medical Devices; compatibility of the product when exposed to circulating blood and infections; and shelf life.
There are many different recipes for priming solutions using crystalloid, colloid or blood as primary constituents. Historically, blood was used to prime the CPB circuit in an attempt to preserve a high hematocrit; early in the evolution of CPB this was thought to be an important determinant for successful outcome. It later became clear, however, that use of allogenic blood in the prime may have worsened, rather than improved, outcomes. In 1962, Cooley and co workers showed improved outcome by adding 5% dextrose to the prime instead of just blood. Five percent dextrose later fell out of favor for two reasons: firstly, the realization that metabolism of glucose leads to a hypotonic solution; and secondly, fears about hyperglycemia worsening neurological outcome. In part, accumulation of knowledge about the deleterious effects of blood primes and acceptance that a lower hematocrit is compatible with good outcomes has led to acceptance of crystalloids as priming solutions. The introduction of hypothermic bypass in the 1960s, the inability of blood banks to support cardiac surgery with large amounts of whole blood and the prevalence of blood-borne infections were also important in the shift to “clear” primes . In general, an ideal priming solution should have the same tonicity, electrolyte composition and pH as that of plasma. Of these ideal properties the most important is that of “tonicity,” in order to avoid red cell lysis and the fluid shift s from the extracellular to the intracellular compartment that occur with hypotonic solutions. Fluid shifts may occur in any organ or tissue, but the organs most vulnerable to fluid accumulation are the brain and lungs. Intracellular fluid gain causes cerebral or pulmonary edema and impairs organ function. It is important to appreciate that fluids which are nominally isotonic but which have glucose as a major constituent, e.g., 5% dextrose or dextrose/saline, become very hypotonic when the glucose is metabolized. For this reason, glucose-containing solutions should not be a major constituent of a prime and only those fluids with a near physiological sodium concentration should be used.
Suitable solutions used include lactated Ringer’s (Hartmann’s), Ringer’s, normal saline, Plasma-Lyte and Normosol (see Tables 3.1 and 3.2 ). All of these solutions have similar sodium concentrations (130–150 mmol/l) and may contain physiological concentrations of potassium (Hartmann’s, Plasma-Lyte). There are some differences in anion composition, but all have chloride as a major anionic constituent, the balance in Hartmann’s or Plasma-Lyte being made up with lactate or acetate, respectively. Both lactate and acetate are ultimately metabolized to bicarbonate in the liver, thus producing a near ideal physiological solution. Hartmann’s solution is the most commonly used crystalloid in priming fluids in the UK, although there is variation in practice amongst different units. Normosol-A and Plasma-Lyte are balanced solutions more commonly used in the USA.
The priming solution has been implicated as one of the potential causes of the disturbance of pH associated with development of metabolic acidosis on initiation of CPB. This acidosis is probably caused by hyperchloremia and is more likely to occur with normal saline, which has a higher chloride load than the more “physiological” solutions. Other possible reasons for this include an increase in unmeasured anions such as acetate and gluconate. This metabolic acidosis is a benign phenomenon and probably accounts for much of the base deficit observed while on bypass.
Colloid solutions, including 4.5% albumin, gelatins, e.g., gelofusine, dextrans and starches, e.g., hydroxyethyl starch, have been advocated for use in the CPB prime on account of their potential to counteract the decrease in colloid oncotic pressure associated with hemodilution of albumin and other circulating plasma proteins during CPB. This reduction in colloid oncotic pressure causes movement of water out of the intravascular space and into the interstitial and intracellular spaces, contributing to postoperative edema and subsequent organ dysfunction. Thus, using colloids, with their high molecular weight, to maintain oncotic pressure and therefore reduce fluid shifts seems an attractive strategy. The drawback to this hypothesis is that whilst, in theory, colloid solutions ought to remain in the intravascular space, in practice the “tight junctions,” which render the endothelial lining impermeable to large molecules, become more permeable on activation of the systemic inflammatory response associated with CPB. This may paradoxically increase the amount of extravasated fluid, as the high-molecular-weight constituents of colloid solutions become trapped in the interstitial fluid, potentially adding to edema by
drawing more free fluid into the interstitium. Furthermore, some of the constituents of colloids have undesirable properties: dextrans interfere with coagulation, starches may remain in the body for years, with unknown long-term consequences and albumin solutions are in scarce supply and pose infection hazards. Cost and availability are also an issue with colloid solutions. The use of colloid-based primes has not been shown to significantly influence clinical outcomes such as the duration of ventilatory support and length of intensive care unit (ICU) or hospital stay. None of the types of colloids has been shown to have significant advantages over another. Albumin may have a beneficial effect as a constituent of the prime: it is thought to coat the extracorporeal circuit, making it appear less “foreign” to the body’s immune mechanisms and so to ameliorate the inflammatory response. The lack of measurable benefit, potential risks and the significant cost penalty incurred in comparison to crystalloid fluids have resulted in colloids no longer being widely used as a priming fluid in adult CPB. The use of mannitol as a colloidal fluid added to the CPB prime is perhaps the one exception to the above discussion. Mannitol is a common constituent of primes, but the indication for its use is for its properties as a potent osmotic diuretic, rather than to simply raise
the oncotic pressure of the prime. Maintenance of urine output both during CPB and in the immediate postoperative period is desirable to enhance elimination from the body of the fluid load presented by prebypass iv fluids, the priming fluid volume and cardioplegia solution. It has also been postulated that mannitol may help to preserve renal function and reduce the incidence of post-CPB renal dysfunction, although the evidence for this is extremely weak. In The use of colloid-based primes has not been shown to significantly influence clinical outcomes such as the duration of ventilatory support and length of intensive care unit (ICU) or hospital stay. None of the types of colloids has been shown to have significant advantages over another. Albumin may have a beneficial effect as a constituent of the prime: it is thought to coat the extracorporeal circuit, making it appear less “foreign” to the body’s immune mechanisms and so to ameliorate the inflammatory response.
Cardiopulmonary bypass circuits comprise of a large surface area of mainly plastic material, which if left to come into contact with blood without appropriate anticoagulation, would result in formation of clots within the circuit in a matter of minutes. In order to safely conduct/CPB for the duration required for surgical procedures, or to maintain patients on extracorporeal support, anticoagulation must be adequate to prevent the development of even “minor” clots. Inadequate anticoagulation can in its most serious form lead to death and in lesser forms lead to impairment of organ function, usually manifest as neurological or renal dysfunction. Furthermore, any clots within the CPB system can trigger the development of disseminated intravascular coagulation (DIC), which results in the rapid consumption of clotting factors and failure of the body’s coagulation system.
Heparin is the most commonly used anticoagulant in the context of CPB. Th is chapter describes the coagulation pathway, the pharmacology of heparin, monitoring of anticoagulation status, problems associated with heparin usage, alternatives to heparin, the reversal of anticoagulation following termination of CPB and the prevention and management of bleeding .
Mechanism of anticoagulant action
Heparin contains a specific pentasaccharide sulfation sequence that binds to the enzyme inhibitor antithrombin III (AT-III) causing a conformational change that results in increasing AT-III’s activity. The activated AT-III then inactivates thrombin and other proteases involved in blood clotting. These factors include IIa (thrombin), Xa, IXa, XIa and XIIa. It is most active against thrombin and Xa. The rate of inactivation of these proteases by AT-III can increase by up to 1000-fold due to the binding of heparin. In addition, heparin increases the activity of heparin cofactor II, which also inhibits thrombin. Heparin’s onset is immediate and has a half-life of approximately 2.5 hours at doses of 300–400 USP units (U)/kg. It is provided in units, with 1 U, according to the US Pharmacopoeia, maintaining fluidity of 1 ml of citrated sheep plasma for 1 hour after recalcification.
Dosing
Dosing of heparin can vary among institutions. The most common initial dose for CPB is 300–400 USP U/kg. Some centers base the initial dose on a bedside ex vivo heparin dose-response titration. Many institutions add heparin to the CPB priming solution at approximately the same concentration as that of the patient’s bloodstream or as a fixed dose. Supplemental heparin doses are guided by monitoring of anticoagulation using the activated clotting time (ACT) or heparin concentration monitoring.
Monitoring
The ACT is a funtional assay of heparin anticoagulation and is the most widely employed test. Most institutions use a level between 400 and 480 seconds as an acceptable ACT level at which to conduct CPB. Hypothermia, hemodilution, platelet function abnormalities and low fibrinogen are some of the factors that can prolong ACT, even in the setting f incomplete heparinization. ACT monitoring will be discussed in further detail under the section “Pointof- care testing.”
Heparin resistance Heparin resistance is defined as failure to raise the ACT to expected levels despite an adequate dose and plasma concentration of heparin. Clinical conditions involving congenital or acquired AT-III deficiency are associated with heparin resistance. Hemodilution during CPB can decrease AT-III levels, though usually this does not result in heparin resistance because it is also associated with dilution of procoagulant factors. Prior treatment with heparin causes depletion or dysfunction of AT-III and this is the most likely reason that cardiac surgery patients will present with heparin resistance. Another cause of heparin resistance is the presence of large quantities of heparin-binding protein in the circulation, which binds to and inactivates heparin.
Administering additional heparin boluses of up to 600–800 USP U/kg may be necessary to obtain an ACT level sufficient for the conduct of CPB. Definitive treatment is aimed at increasing levels of AT-III. This can be done by administering fresh frozen plasma (FFP), which contains antithrombin; however, exposure to transfusion-borne infectious diseases is a risk. Supplemental AT-III concentrate is another alternative and provides greater protection against disease transmission than FFP. AT-III is also available in recombinant formulations, which have been used to treat congenital deficiency.
Heparin-induced thrombocytopenia (HIT)
Heparin-induced thrombocytopenia (HIT) develops in 5% of patients receiving heparin and is categorized into two subtypes. Th e fi rst type is generally mild and involves a transient decrease in platelet count. Th ese patients can safely receive heparin for cardiac surgery. Th e second type occurs later in heparin therapy (5–14 days aft er dministration) and is a more severe, immune-mediated decrease in the platelet count. Antibodies against the complex of platelet factor 4 (PF4) and heparin bind to platelets, activate the platelets and cause the resultant platelet count to drop precipitously. In the setting of endothelial injury, this enhancement in platelet activation predisposes to the formation of platelet clots (white clots) and thrombosis.Heparin-induced thrombocytopenia is a clinicopathological syndrome and requires both clinical evidence thrombocytopenia or thrombosis) and laboratory fi ndings to confi rm the diagnosis. Laboratory diagnosis can be made in two ways: functional assay or antibody-based assay. Functional tests detect heparin-dependent platelet activation in the presence of the patient’s sera and UFH. Th e serotonin release assay (SRA) is considered the gold standard: when an aff ected patient’s serum is exposed to heparin, an exaggerated reaction occurs and serotonin is released from dense granules. Using C-14-labeled serotonin the concentration released is then measurable. Other functional tests include the heparin-induced platelet activation assay (HIPAA) and the platelet-rich plasma (PRP) aggregation assay , which measure hyper-aggregability in response to heparin. Enzyme-linked immunological assays measure IgG, IgM or IgA antibodies that bind to the PF4/heparin complex. Th e Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Th rombolytic Th erapy resulted in the publication of evidence-based guidelines. Recommendations were made for patients undergoing cardiac surgery with previous HIT, as well as those with acute or subacute HIT. Grade 1 recommendations are trong and indicate that a high level of evidence suggests that the benefi ts of a particular intervention outweigh the risks, burden and costs. Grade 2 recommendations suggest that individual patients’ or physicians’ values may lead to diff erent choices. Management of these patients can be summarized as follows: Patients with a history of HIT who are antibody negative and require cardiac surgery can receive unfractionated heparin. For patients with acute HIT who require cardiac surgery, the guideline developers recommend delaying surgery, if possible, until HIT antibodies are negative or using alternative anticoagulant approaches such as bivalrudin or hirudin. Combinations of unfractionated eparin and antiplatelet agents such as epoprostenol or tirofiban are also recommended . Alternatives to unfractionated heparin
Low-molecular-weight heparin (LMWH)
Intravenously administered LMWH has a half-life at least twice as long as that of UFH and possibly several times as long for some LMWH compounds. Problems during CPB arise fro the fact that protamine neutralization only reverses the factor IIa inhibition and leaves the predominant factor Xa inhibition intact. LMWH therapy also complicates heparin monitoring because activated partial thromboplastin time (APT) (and presumably ACT) is much less sensitive to Xa inhibition and will not accurately measure the full anticoagulant eff ect. Factor Xa inhibition can be measured, but not with a simple bedside test. LMWHs are not recommended for use in HIT patients
Danaparoid
Danaparoid is a low-molecular-weight heparinoid with a long half-life (18–24 hours). It is a polysulfated glycosaminoglycan composed of heparan sulfate (84%), dermatan sulfate (12%) and chondroitin sulfate (4%). Th ere is a 30% cross-reactivity with heparin antibodies, which precludes its use in HIT patients. Monitoring is via anti-Xa levels and currently there is no antidote. It has been studied in CPB and has not been proven to be safe because of excess bleeding and thrombosis. Danaparoid is no longer available in the USA.
Fibrinolytics
Ancrod (viprinex) is a defi brinogenating agent extracted from Malayan pit viper venom. Fibrinogen levels must be <500 mg/l prior to instituting CPB, which requires more than 2 hours aft er administering Ancrod to be achieved. Other disadvantages include no antidote, lack of monitoring and bleeding complications. Ancrod is not recommended for use in HIT patients.
Direct thrombin inhibitors (DTIs)
Th ese directly inhibit the procoagulant and prothrombotic actions of thrombin and do not require a cofactor. Th eir advantage is that they do not interact with or produce heparindependent antibodies. Th e main diff erences between the two types of thrombin inhibitors are listed in Table 4.1
• Lepirudin – Th is is a recombinant analogue of the anticoagulant hirudin produced in leech saliva. It has a short half-life of 80 minutes and is monitored via activated partial
thromboplastin time (aPTT) or ACT and has no antidote. It can, however, be eliminated by hemofi ltration. Lepirudin is metabolized by the kidney requiring dose adjustments in patients with renal insuffi ciency. Th e advantage is that it lacks cross-reactivity with heparin but antihirudin antibodies develop in as many as 60% of patients. Current evidence suggests that these antihirudin antibodies do not interfere with the anticoagulant activity of hirudin and their signifi cance is unknown. • Argatroban – Th is is a synthetic molecule derived from L-arginine and is widely used in patients with HIT who require percutaneous coronary intervention. Its half-life is 45–55 minutes, it lacks cross-reactivity with heparin antibodies and is monitored via the aPTT or ACT. Th ere is no antidote. Argatroban is metabolized in the liver requiring dose adjustments in patients with moderate liver disease. Argatroban has not yet been approved for use in CPB. It is not available in the UK. • Bivalirudin – Th is is a synthetic peptide based on the structure of hirudin. Its advantage is its short half-life of 25 minutes. It is monitored via the aPTT, ACT or ecarin clotting time, if available. Th e dose for CPB is a 1 mg/kg bolus followed by a 2.5 mg/kg/hour infusion. Bivalirudin is metabolized by proteolytic enzymes present in the blood and by the kidney. Only minor dose adjustments are necessary for patients with renal insuffi - ciency. Multicenter trials have demonstrated it is not inferior to heparin when used in CPB. Currently, bivalirudin is widely used in cardiac catheterization laboratories as the anticoagulant for percutaneous coronary intervention, even in patients without HIT .
Several protamine dosing techniques have been utilized. Th e recommended dose range of protamine for heparin reversal is 1–1.3 mg protamine per 100 U of heparin. Other pproaches include calculating the protamine dose based on the heparin dose–response curve generated by some automated systems such as the Hepcon (Medtronic Inc). Protamine must be administered slowly in order to prevent adverse hemodynamic eff ects such as hypotension. Protamine reactions have been classifi ed into three types. A Type I reaction may result from rapid administration resulting in decreases in both systemic and pulmonary arterial pressures, decreased preload and hypotension. Th e Type II reaction is immunological and is categorized as IIA anaphylaxis, IIB anaphylactoid and IIC non-cardiogenic pulmonary edema. Type III reactions are caused by heparin/protamine ionic complexes that can adhere in the pulmonary circulation and cause pulmonary vasoconstriction. Th is results in catastrophic pulmonary hypertension and resultant right heart failure. Adequacy of neutralization should be assessed by repeating ACT 3–5 minutes aft er reversal.
Type I reaction may result from rapid administration resulting in decreases in both systemic and pulmonary arterial pressures, decreased preload and hypotension.
The Type II reaction is immunological and is categorized as IIA anaphylaxis, IIB anaphylactoid and IIC non-cardiogenic pulmonary edema.
Type III reactions are caused by heparin/protamine ionic complexes that can adhere in the pulmonary circulation and cause pulmonary vasoconstriction. This results in catastrophic Pulmonary hypertension and resultant right heart failure
Alternatives to protamine
Hexadimethrine This synthetic polycation can be administered to patients who are allergic to protamine without adverse eff ects. However, when administered rapidly, hexadimethrine mimics the response to rapid administration of protamine because it forms complexes with heparin. Systemic hypotension, decreased systemic vascular resistance (SVR) and pulmonary vasoconstriction are among the adverse reactions seen. Following reports of renal toxicity, hexadimethrine was withdrawn from clinical use in the USA.
Platelet factor 4 (PF4) Platelets contain PF4, a potent antiheparin compound, on their surface, which utilizes lysine residues at it C-termini to neutralize heparin, rather than the electrostatic binding that occurs with protamine. It is hypothesized that the cause of heparin-induced thrombocytopenia is an immunological
reaction to the PF4/heparin complex.
Methylene blue Th is chemical dye binds electrostatically to heparin in a similar fashion to protamine. Large doses do not eff ectively restore the ACT to normal. An inhibitor of nitric oxide synthetase,
Heparin DTIs Mode of action Indirect Direct Cofactor needed Yes – AT-III No Inhibits clot-bound thrombin No Yes Activates platelets Yes No
Antigenicity Yes No – bivalirudin; Yes – hirudin
Antidote drug Yes – protamine No
methylene blue increases pulmonary and systemic vascular resistance at higher doses,
making its use quite hazardous.
Omit neutralization
Due to drug elimination, heparin will dissipate spontaneously with time with consequent decline in anticoagulation. Th is option may result in an increase in transfusion requirements, hemodynamic instability and consumptive coagulopathy as a result of hemorrhage and transfusions.
Heparinase Heparinase, an enzyme produced by the gram-negative Flavobacterium , hydrolyzes the heparin molecule into smaller inactive fragments. Some of these small fragments do possess the potential for some anti-Xa activity, thus the utility of heparinase in reversing heparin aft er CPB is limited
Point-of-care testing (POC)
Point-of-care testing devices allow the monitoring of hemostasis at “the bedside” rather
than sending specimens to a central laboratory facility. Th ese instruments rapidly assess
coagulation and/or platelet function to aid in providing appropriate targeted therapy. As
a result there is a reduction in blood loss and transfusion, fewer complications and cost
reduction.
Th e ACT is an automated variation of the Lee–White clotting time and is the most commonly
used test to measure heparin anticoagulation. It uses an activator such as celite or
kaolin to activate clotting, then measures the clotting time in a test tube or cartridge. Normal
baseline ACT levels, without any heparin in the blood, should be between 80 and 140 seconds.
For CPB, prolongation of the ACT to greater than 400 or 480 seconds is considered adequate,
though this is highly debated. For off -pump coronary artery bypass operations (OPCAB) ,
“partial heparinization” may be used in some centers whereby an ACT greater than 300 seconds
is targeted. The Hemochron (International Technidyne Corp, Edison, NJ, USA) and
the HemoTec ACT (Medtronic HemoTec, Parker, CO, USA) are two automated ACT devices
used in the operating room.
During CPB the sensitivity of the ACT to heparin is altered by hemodilution and hypothermia.
As a result ACT measurements do not correlate with heparin concentration or with
antifactor Xa activity. The Hepcon HMSR analyzer (Medtronic Inc, Minneapolis, MN, USA)
uses protamine titration assays to determine the blood heparin level. Th is device can also
provide a dose–response curve for an individual patient and indicate how much heparin to
administer in order to reach a specifi c targeted ACT before going onto CPB. In addition, it can
be utilized for protamine dosing aft er CPB
The “performance index” of an arterial cannula is the pressure gradient versus the outer diameter at any given flow. The narrowest portion of the catheter that enters the aorta should be as short as safely possible and the diameter should then gradually increase in size to minimize the gradient. Pressure gradients greater than 100 mmHg can cause excessive hemolysis and should be avoided.
On occasions, blood can return from abnormal sources. These include:
• left -sided SVC;
• patent ductus arteriosus (PDA);
• atrial septal defect/ventricular septal defect;
• anomalous venous drainage;
• aortic regurgitation; and
• systemic to pulmonary shunt.
Venting the left heart
The left ventricle needs to be vented if it is filling from any source but not ejecting. It will fi ll primarily because of aortic insufficiency, or during cardioplegia administration. Venting:
• prevents distension of the ventricle;
• reduces myocardial re-warming;
• prevents ejection of air; and
• provides a bloodless surgical field.
In adults at normothermia, clinical and experimental data support a minimum flow index of 1.8 l/minute/m 2 . Kirklin and Barratt-Boyes recommended a flow index of 2.2 l/minute/m 2 for adults at a temperature of 28°C or above. Th e patient’s body surface area (m 2 ) is worked out from a normogram plotting height in meters and weight in kilograms. Patients with a body surface area greater than 2 m 2 should have the flow maintained at 1.8–2.2 l/minute/m 2 to avoid excessively high flows through the machine leading to hemolysis.
STANFORD, Calif. — Norman E. Shumway, MD, PhD, the father of heart transplantation and one of the pre-eminent heart surgeons of his time, died Feb. 10 at his Palo Alto home of complications from cancer, the Stanford University School of Medicine announced. He celebrated his 83rd birthday the previous day on Feb. 9.
Shumway, professor emeritus of cardiothoracic surgery, performed the first successful human heart transplant in the United States in 1968 at Stanford. The recipient, 54-year-old steel worker Mike Kasperak, lived for 14 days.
The landmark operation created a burst of enthusiasm for heart transplantation, though cardiac surgeons quickly lost interest because of the high rate of post-surgical deaths.
Shumway nonetheless persevered in the field amid controversy over legal and economic issues, particularly the issue of what constitutes brain death among potential donors. For nearly a decade, Stanford stood virtually alone as the only center performing the pioneering operation. Shumway and his colleagues made steady progress, paving the way for a procedure considered routine today.
“Many people gave it up when they thought it was too difficult, but Dr. Shumway had the persistence and vision that it could work. His determination to make heart transplantation work was absolutely crucial,” said Bruce Reitz, MD, the Norman E. Shumway Professor of Cardiothoracic Surgery at Stanford and former chair of the department.
Nearly 60,000 patients in the United States have enjoyed longer lives because they received new hearts through transplant programs at some 150 medical centers around the country. At Stanford, some 1,240 patients have benefited from heart transplants.
Shumway, a reticent man who did not like to tout his accomplishments, told a crowd of transplant patients at a 2003 Stanford reunion that it was “gratifying to see the changes that have made this (heart transplant) an almost ordinary experience.” At the reunion party, which also marked his 80th birthday, he praised the patients, saying, “You made us look good.” He called them “the real heroes … so marvelous, so strong, so courageous.”
Office of Communication & Public Affairs
Norman Shumway, MD, PhD, was the father of heart transplantation and one of the pre-eminent heart surgeons of his time.
Philip Pizzo, MD, dean of Stanford School of Medicine, called Shumway “one of the 20th century’s true pioneers in cardiac surgery.”
“He developed one of the world’s most distinguished departments of cardiothoracic surgery at Stanford, trained leaders who now guide this field throughout the world and created a record of accomplishment that few will ever rival. His impact will be long-lived and his name long-remembered,” Pizzo said. “We will miss Norm Shumway and the dignity and excellence that he brought to medicine and surgery — and to Stanford.”
Shumway, the Frances and Charles Field Professor of Cardiovascular Surgery, Emeritus, cherished the fact that he had trained so many of the world’s leading cardiac surgeons who went on to direct departments of their own at major medical centers. His approach, contrary to the conventions of the time, was to step back from the spotlight and give his young trainees major responsibility in the operating room, greatly improving the learning experience.
“I never worked so hard in my life and never learned so much and had so much responsibility at a young age,” said William Brody, MD, PhD, president of Johns Hopkins University and a Shumway trainee. “He was a brilliant teacher and a master psychologist. With his humor, he always made it fun. To be in the operating room with Shumway was the height of your day because he was brilliant and witty. At a time when everybody made cardiac surgery seem complex, he made it seem easy.”
Shumway, who was born in Kalamazoo, Mich., did not start out to become a physician. He entered the University of Michigan in 1941 intending to study law but left two years later after being drafted into the Army. In the military he was given an aptitude test that asked him to check a box for a career interest: medicine or dentistry. He chose the first and was enrolled in a specialized Army program that included pre-medical training at Baylor University in Texas. He moved on to Vanderbilt University, where he received his MD in 1949.
He did his internship and residency at the University of Minnesota, where he developed an intense interest in cardiac surgery. After another two-year stint in the military, this time the Air Force, he continued his surgical training in Minnesota and obtained his PhD in cardiovascular surgery in 1956.
Chuck Painter, Stanford News Service
Shumway (left) and Donald Harrison meet the press after they perform the first adult human transplant in the United States on Jan. 6, 1968. The recipient, 54-year-old steel worker Mike Kasperak, lived for 14 days.
Shumway came to Stanford in 1958 as an instructor in surgery. Shortly after his arrival, the medical school moved from San Francisco to Palo Alto, giving Shumway the opportunity to launch the cardiovascular surgery program at the new, expanded campus.
In 1959, working with then-surgery resident Richard Lower, MD, he transplanted the heart of a dog into a 2-year-old mongrel. The transplanted dog lived eight days, proving it was technically possible to maintain blood circulation in a transplant recipient and keep the donated organ alive. Shumway and his colleagues would spend the next eight years perfecting the technique in dogs, achieving a survival rate of 60 to 70 percent.
“We started out doing this as a technical exercise and the animals began to survive,” he said years later.
In 1967, he announced that he was confident enough in the research to start a clinical trial and that Stanford would perform a transplant in a human patient if a suitable donor and recipient became available. Shortly thereafter, Christiaan Barnard, MD, of South Africa performed the world’s first heart transplant on a patient who lived for 18 days, using the techniques Shumway and Lower had developed.
On Jan. 6, 1968, Shumway did his landmark first procedure which — to his chagrin — attracted worldwide media attention, with journalists climbing the walls of the hospital to try to get a peek into the operating room.
Years later, Shumway said of the transplant: “We put in the heart and nothing happened. There were slow waves on the EKG and then the heart began beating stronger and then exuberance…. We knew we would be okay.”
Edward Stinson, MD, the then-chief resident in cardiac surgery who assisted Shumway, described the operation as “pretty awe-inspiring.”
“After we removed the recipient’s heart, we stared at the empty pericardial cavity and wondered what we’d actually done,” recalled Stinson, professor emeritus of cardiothoracic surgery at Stanford. “His (Shumway’s) wit always came through, no matter how challenging the circumstances. He said, ‘I’m not sure. Time will tell.’ We proceeded with implanting the new heart. It was pretty exciting to see it start up.”
John Sheretz
At the 2004 transplant reunion, Shumway (right) talks with Danilo Oncena, who underwent two heart transplants at Stanford. It was the last such reunion that Shumway attended.
Shumway and his colleagues made steady progress over the next decade through careful selection of donors and recipients, efforts to increase the donor pool, improvements in organ preservation and in heart biopsies and advances in drugs to prevent rejection of the foreign organ, among other developments. His team was the first to introduce cyclosporine for heart transplantation in late 1980. With the availability of immunosuppressive drug, which is still in use today, the field took a giant leap forward.
In 1981, Shumway and Reitz performed the world’s first successful combined heart-lung transplant in 45-year-old advertising executive Mary Gohlke, who lived five more years and wrote a book about her experiences. By the late 1980s, they were transplanting hearts into infants as well.
Shumway rose to become chief of the division of cardiothoracic surgery at Stanford in 1965 and in 1974, he negotiated the creation of a separate Department of Cardiothoracic Surgery, which he chaired until his retirement in 1993.
His accomplishments were not limited to the field of transplantation. Shumway also made significant contributions to treatment of congenital heart problems in children, as well as valve problems and aneurysms in adults.
Over the years, Shumway received dozens of honors and awards. In 1980, he was named honorary president for life by the International Society of Heart and Lung Transplantation. He also has received the Scientific Achievement Award from the American Association for Thoracic Surgery, the American Surgical Association, and the American Medical Association, as well as the Trustees Medal for Distinguished Achievement from Massachusetts General Hospital, to name a few.
He is survived by his former wife, Mary Lou, of Palo Alto; four children—Sara, Lisa, Amy and Michael; and two grandchildren. The family requests that any memorial donations be made to the Stanford University Heart Transplant Patient Care Fund, in care of the Department of Cardiothoracic Surgery, 300 Pasteur Drive, Falk Building, Stanford, CA, 94304-5407.
Alpha- stat and pH-stat strategies for blood gas management The optimal pH management strategy during hypothermic cardiopulmonary bypass is as yet undetermined. The two main strategies utilized clinically, alpha-stat and pH-stat, differ in their approach to the acid–base alterations that occur with hypothermia. As blood temperature falls, gas solubility rises and the partial pressure of carbon dioxide decreases (PCO 2 decreases 4.4% for every °C drop in temperature). With alpha-stat management, arterial gas samples are not corrected for sample temperature and the resulting alkalosis remains untreated during cooling; with pH-stat management, arterial blood gas samples are temperature corrected and carbon dioxide is added to the gas inflow of the CPB circuit so that the PCO2, and hence pH, is corrected to the same levels as during normothermia. The advocates of alpha-stat point to potential benefits in terms of the function of intracellular enzyme systems and the advantage of preserving cerebral autoregulation. Proponents of pH-stat, which results in cerebral vasodilation, cite as advantages higher levels of oxygen delivery to the brain and enhanced distribution of blood fl ow. However, the higher cerebral blood flows associated with pH-stat also have the potential to carry more gaseous or particulate emboli to the brain. Alpha-stat management is based on the concept that the dissociation constant, pK, of the histidine imidazole group changes with temperature in a manner nearly identical to physiological blood buffers. Hence, the ionization state ( α ) of this group stays the same, irrespective of temperature. As the imidazole group’s ionization state is a key determinant of intracellular protein function, advocates of alpha-stat management contend that this strategy promotes normal protein charge states and function, even at low temperatures. The pH-stat approach increases the total carbon dioxide content of the blood as the temperature falls in order to maintain fixed temperature-corrected pH values. The optimal pH of most enzymatic reactions does vary with hypothermia, mostly in accordance with the predictions of the alpha-stat hypothesis. Hence, the relative acidosis of pH-stat would be expected to
lower enzymatic reaction rates. Whether this is beneficial in reducing energy consumption, or harmful by impairing key cellular homeostatic mechanisms, is unclear. Differences in alpha-stat and pH-stat management become progressively greater as temperature is reduced so the effect is quite profound below 25°C, but above 32°C, quantitatively, the change in CO 2 solubility is small and of much less clinical and physiological relevance. This is further evident when one appreciates how little CPB time most adult cardiac surgical patients spend at hypothermic temperatures. Most cases are conducted with mild hypothermia and in those much of CPB time is spent transitioning to, or from, those temperatures; the actual time on CPB spent below 32°C may only be 25% of the total CPB time. Thus, although frequently discussed, alpha-stat versus pH-stat management is of little actual relevance in most adult cardiac surgery. Electrolytes Potassium (K + ) Hyperkalemia is the most common electrolyte disturbance during CPB. Potassium levels can be lowered using diuretics, insulin and dextrose administration, or hemofiltration. The treatment of choice is dictated by the potassium level, the persistence of rise in potassium levels and the presence or absence of electrophysiological disturbances. Serum potassium levels transiently rise with the administration of cardioplegia and this will usually correct without treatment within a short period aft er ceasing delivery of cardioplegia. Potassium levels in the range 5.5–6.5 mmol/l can be treated with administration of a diuretic, usually furosemide 20–40 mg. In some centers, levels between 6.5 and 7 mmol/l are treated using insulin and dextrose infusions. Levels above 7 mmol/l or persistently raised potassium levels can be lowered using “zero balance hemofiltration.” A crystalloid solution, typically normal saline, is added to the CPB circuit to maintain circulatory volume and then removed by hemofi ltration causing concomitant removal of potassium. As this technique can result in the loss of signifi cant amounts of bicarbonate through the hemofi lter, it should be replaced using sodium bicarbonate titrated to blood bicarbonate levels. Th e urgency or need to treat hyperkalemia should in part be determined by the presence or absence of electrophysiological disturbance. In the absence of ECG changes, moderate hyperkalemia may not require treatment. If treatment is chosen, its eff ect should not be longer than the anticipated period of hyperkalemia. It is important to note that during CPB extracellular potassium may rise but typically, even untreated, increases in K + levels are nearly always transient, as the extracellular potassium concentration in the plasma is quite small relative to the intracellular capacity for its uptake. Rapid shift s to the intracellular space and urinary excretion oft en correct K + levels quite quickly aft er CPB. Hypokalemia, usually less than 4.5 mmol/l, is treated by administration of potassium chloride, normally in 10–20 mmol boluses. It is worth bearing in mind that rapid bolus administration of potassium during CPB may cause transient vasodilatation. Potassium levels alter with temperature. Treatment should be undertaken in the context of: • temperature;
• the rate of rise of the potassium level; • the persistence of that level; and • the point during surgery at which it is occurring. Ideally, potassium is fi nally corrected before separation from CPB using results of electrolyte measurements taken at a body temperature of not less than 35°C. Calcium (Ca 2+ ) Calcium levels are reduced by hemodilution, chelation by preservatives in bank blood or by hemofi ltration. Low serum Ca 2+ levels are generally corrected close to the termination of CPB, when the aortic cross-clamp has been removed, a cardiac rhythm has been established and the temperature is approaching normothermia. One gram (or 3–5 mg/kg) of calcium chloride is
usually all that is required to normalize serum ionized calcium levels (1–1.5 mmol/l). Administration of Ca 2+ may exacerbate reperfusion injury and should be avoided immediately before or aft er cross-clamp removal. Timing of administration can be guided by normalization of cardiac conduction indicating adequate reperfusion. Magnesium (Mg + ) Magnesium depletion occurs during CPB if hemofi ltration is used or if there is high volume diuresis, particularly with loop diuretics. In these situations, a 2 mg bolus of Mg + may be added empirically into the circuit aft er the core temperature has reached 34°C and the aortic cross-clamp has been removed. Ideally, if Mg + levels are available, Mg + administration should be titrated according to blood levels. Phosphate Phosphate levels are commonly low aft er major cardiac surgery. Th is frequently occurs inthe immediate postoperative period and is associated with signifi cant respiratory and cardiac morbidity. Th erefore, phosphate levels should be routinely measured aft er surgery, especially in patients with a complicated or prolonged intraoperative course, so that appropriate replacement therapy may be started in a timely manner. Glucose Phosphate levels on CPB tend to increase as a result of the physiological stress response to major surgery. Values may exceed 20 mmol/l in diabetic patients without treatment. Nondiabetic
patients’ serum glucose levels can also rise; levels of 10–15 mmol/l are not uncommon. Continuous insulin infusions of 5–15 U/hour may be required during CPB. Hyperglycemiais associated with poor patient outcomes. Specifi cally, perioperative hyperglycemia has been associated with higher incidences of mediastinitis, wound infections and neurocognitive deficits. Confl icting literature regarding both the ideal and acceptable intraoperative and postoperative glucose levels exists. However, recent studies have shown mixed results from attempts at aggressive management of CPB-related hyperglycemia. Th e results range from favorable outcomes, to little or no association between reducing serum glucose levels and reduction in postoperative complications, to adverse patient outcomes associated with the tight control of CPB-related hyperglycemia. It is generally believed that normal (4.0–5.5 mmol/l) serum glucose levels during CPB are ultimately desirable. Consistent achievement of this goal remains elusive at this time. Postoperative hypoglycemia, equally as dangerous and undesirable as hyperglycemia, can result from clinicians “overshooting” in their attempts at serum glucose reduction.
Lactate
Lactate is a major end product of glucose metabolism and gives an indication of the metabolic status during CPB. Most patients exhibit a progressive increase in plasma lactate during CPB. Lactate levels increase two- to threefold during normothermic and hypothermic CPB. During periods of hypoperfusion or decreased liver function, usually secondary to hypothermia, serum lactate levels can increase even further (four- to eightfold). Re-warming the patient and increasing fl ow rates usually helps to lower lactate levels.
Table 5.7. Checklist before weaning from CPB
Patient position on operating table is neutral
Operation completed and vent sites closed
Hemostasis secured
Heart de-aired (confi rmed with TOE if available)
Ventilation of lungs recommenced and adequate
Acceptable Hb/HCT, potassium, glucose, and acid–base status on arterial blood gas analysis
Acceptable core temperature achieved
Heart rhythm and rate appropriate
Parameters for initial fi lling pressure when off CPB are determined
Inotropic support prepared if necessary
Functional mitral regurgitation
Acute mitral regurgitation in a patient with a morphologically normal mitral valve is occasionally encountered during and aft er weaning from CPB. Although infrequent, it usually
occurs in patients undergoing coronary revascularization. Th is phenomenon, functional mitral regurgitation, is readily treatable with an excellent outcome, but can be surprisingly diffi cult to identify. Failure to recognize and treat it appropriately may lead to considerable morbidity. As mentioned previously, weaning from CPB should be accomplished with a low ventricular fi lling volume and pressure, allowing the heart time to accommodate to the changing loading conditions. If CPB is terminated rapidly with high venous pressures and ventricular volumes, the left ventricle may become relatively ischemic and dilate. As a result the mitral valve annulus will be stretched, rendering the mitral valve acutely incompetent; the right ventricle faces acute left atrial hypertension and will appear characteristically dilated and domed, with limited contraction and no eff ective dimpling of its anterior surface. More commonly than this sudden scenario, the development of functional mitral regurgitation is insidious and the result of overzealous fl uid infusion to treat low systemic arterial pressures. A further fl uid challenge in this state characteristically results in a fall in systemic pressure. Adrenaline administration may increase the systemic diastolic pressure through vasoconstriction, but usually makes both the mitral regurgitant fraction and oxygen demand of the left ventricle much worse. Typically, even in a patient with previously preserved left ventricular function, systemic hypotension intractably persists and the condition rapidly becomes a medical emergency. Th e diagnosis is confi rmed by TOE, if available, but the condition occurs typically in patients with low-grade indication for TOE. In the absence of TOE in situ, it is confi rmed by direct left atrial pressure
measurement, characteristically displaying a peak mitral regurgitant systolic wave of the order of 50–70 mmHg. Th e treatment for functional mitral regurgitation is venodilatation, using nitroglycerine (GTN) or sodium nitroprusside, to rapidly reduce the left ventricular end-diastolic volume. Venodilatation is inevitably accompanied by arteriolar vasodilatation and, as eff ective coronary blood fl ow must be restored, aggressive venodilatation should be followed by a short-acting vasoconstrictor. Th e administration of a venodilator to a patient with a mean arterial pressure of 40–50 mmHg may appear counterintuitive, and brave, but is supported by an understanding of the pathophysiology. It is necessary to fi rst reduce ventricular volume and shrink the mitral valve annulus and then support coronary perfusion to the ventricle by raising systemic pressure. Alternative surgical approaches to the management of functional mitral regurgitation may include rapidly returning to cardiopulmonary bypass, performing an atriotomy or draining blood via the CPB cannulae, if still in situ, allowing rapid reduction in circulating volume and left ventricular preload.
Myocardial Protection
Matthew S. Slater
Christopher B. Komanapalli
Howard Song
This chapter will provide an overview of the broad topic of myocardial protection for cardiovascular surgery. Clearly, a single chapter will serve only as an overview; entire books and a large number of publications have addressed the multiple issues related to myocardial protection. Additionally, myocardial protection does not exist in isolation; non-cardiac organ protection for the patient must be considered as well. Techniques that have been used to offset myocardial protection have effects on the other organ systems, and vice versa. Additionally, the development and evolution of myocardial protection have not been linear, most obviously demonstrated by the recent expansion of off-pump techniques for coronary artery bypass grafting (CABG).
The very term myocardial protection implies the potential for myocardial injury of some type, and in regard to cardiac surgery this is manifested as ischemia-reperfusion injury. The pathophysiology and underlying molecular biology of myocardial injury are complex. Ischemia-reperfusion injuries can be broadly grouped into two distinct categories, reversible and irreversible. Reversible injury is manifested by a transient depression in cardiac performance, myocardial edema, and resolves without long-term sequelae. Irreversible cardiac injury involves apoptosis or myocardial necrosis, and results in electrocardiographic changes, release of myocardial-specific enzymes such as creatine phosphokinase (CPK) or troponin into the circulation, and lasting abnormalities of ventricular function, either in hypokinetic or dyskinetic segments of the ventricle.
HISTORY
The last 100 years have witnessed the emergence and development of the field of cardiovascular surgery. This has been paralleled by the development of techniques to protect the heart and allow for the safe conduct of increasingly complex surgeries. The field of cardiovascular surgery is just over 100 years old; in the 1880s, Block began to repair experimental wounds in rabbits (1). However, cardiac surgery was met with skepticism by such prominent surgeons as Billroth and Paget. Despite this criticism and the admonitions from respected surgical leaders, Ludwig van Rehn successfully sutured a right ventricular stab wound in a German man who was attacked in a local park in September 1896, and he subsequently published this experience. In the United States, the first cardiac surgical procedure was a similar case reported by Luther Hill in 1902. The details of this case are consistent with what we now know to be true about cardiac tamponade. When he was called to see a 13-year-old boy, Dr. Hill found him to be in shock with a weak pulse and tachycardia. He opened the chest through a thoracotomy and found the pericardial sac distended with blood. Upon opening the pericardium, he discovered approximately 300 mL of blood and as this was drained strong cardiac function returned. He sutured the wound and the patient survived. Because both of these early experiences were performed for trauma, and were basically resuscitative endeavors, myocardial protection was not even considered (2).
Frederick Trendelenburg devoted a significant amount of time working out the logistics of surgical extraction of pulmonary embolus (3). A series of animal experiments simulating pulmonary embolus and subsequent surgical approaches were carried out using inflow occlusion. Although Trendelenburg was never clinically successful in humans, his student Kirschner (4) successfully performed a pulmonary embolectomy in 1924, with the patient surviving. Again, no consideration of myocardial protection was made; inflow occlusion was simply utilized to provide a semi-bloodless field.
In 1910, Alexis Carrel performed a descending aorta to a coronary artery anastomosis in a dog (5). He noted that 3 minutes after interruption of circulation the ventricle fibrillated. He was able to complete the anastomosis and resuscitate the dog, which subsequently died 2 hours later. He concluded that the anastomosis must be done in less than 3 minutes, and his conclusion was in some ways an oblique reference to the limited ability of the myocardium P.173
to withstand ischemia at normothermia under fibrillating conditions.
TABLE 1 Myocardial Protection Strategies
Delivery Route
Composition
Temperature
Interval
Additives
Monitoring
Additional Strategies
Antegrade
Crystalloid
Warm
Intermittent
Electrolyte
Temperature
Anesthetic agents
Retrograde
Blood
Tepid
Continuous
Pharmacologic
Myocardial pH
Normovolemic hemodilution
Through conduits
Microplegia
Cold
Metabolic
Noncardioplegia medications
Neutrophil depletion
Integrated
Ischemic preconditioning
Off-pump revascularization
Over the next several decades, advances in myocardial protection were closely linked to strategies designed to provide global organ protection, most notably of the brain and kidneys. Bigelow did extensive work with hypothermia in both dogs and ground hogs (6), and Gibbon developed and used a cardiopulmonary bypass (CPB) machine in a series of surgeries on children with congenital heart defects. Gibbon's initial results were disappointing, and he subsequently decided not to continue with the work to develop cardiac surgery using a CPB machine (7). At the same time, the ongoing success of cross circulation at the University of Minnesota by Lillehei, proved the feasibility of heart surgery for the correction of congenital heart defects (8). As CPB technology rapidly improved, cross circulation was abandoned after being used in 45 patients between 1954 and 1955.
With continued advances, more complex cardiac lesions were approached. This required longer periods of cardiac arrest, and this longer period of relatively unprotected ischemia produced greater myocardial injury. Hypothermia was used to extend the period of relative safety. Unfortunately, it became apparent that the myocardium would often be irreversibly damaged, resulting in a “stone heart,” after extended periods of ischemia even with hypothermia. Cross-clamping the heart and thereby depriving it of high-energy phosphate stores eventually led to cardiac arrest, greatly facilitating surgery but producing myocardial damage. It was postulated that chemically arresting the heart would preserve high-energy phosphate stores and provide some measure of myocardial protection. In 1955 and 1957, Melrose described using potassium citrate to induce cardiac arrest. Although somewhat primitive (a 0.5% solution of potassium citrate was drawn into a syringe mixed with blood and injected directly into the aortic root after a cross-clamp had been applied), it did effectively stop the heart (9). Unfortunately, the Melrose solution in isolation did not provide adequate myocardial protection, and was abandoned at many centers in the United States. Adjuncts to this rudimentary form of cardioplegia, such as topical hypothermia, were used to augment myocardial protection with or without chemical cardiac arrest. As a more complete understanding of the requirements for safe cardiac arrest emerged, Hearse et al. in St. Thomas Hospital in London developed the “St. Thomas Solution,” which provided reliable cardiac arrest and reasonable myocardial protection (10). In the 1970s and 1980s the refinement of cardioplegia formulations by Gay and Ebert followed (11). More complex strategies of cardioplegia delivery, including refinements in temperature and route, were described by Follett and Buckberg and this further advanced the efficacy of cardioplegia (12,13).
Currently, an almost infinite number of choices can be considered when choosing a myocardial protection strategy. Although cardioplegic arrest has become the mainstay of myocardial protection, the utility of intermittent fibrillation, off-pump techniques, and deep hypothermic circulatory arrest will be described. This chapter will provide an understanding of the physiology and rationale behind each of these techniques and offer strategies to provide optimal myocardial protection (Table 1).
CARDIOPLEGIA
Delivery Method
Cardioplegia can be delivered in a variety of ways, but the goal remains to provide adequate and uniform distribution of cardioplegia solution to the myocardium (Table 2). Delivery can be extremely simple, direct injection of potassium-containing crystalloid into the aortic root, or can be progressively more complex. Specifically designed “microplegia” systems allow for the modification of flow, pressure, temperature, and even composition of the cardioplegia solution throughout the case (14). The additional control and flexibility that is afforded by more complex strategies must be weighed against the additional expense and potential for confusion that each additional variable introduces. No “best” cardioplegia strategy exists for all circumstances and practice environments; however, a working knowledge of the range of cardioplegia options that are available is useful so that clinicians can provide optimal clinical care.
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TABLE 2 Cardioplegia Delivery Techniques
Technique
Pros
Cons
Antegrade
▪ Simple
▪ Mimics normal coronary flow
▪ Requires competent aortic valve
▪ Advanced CAD
Retrograde
▪ Obviates limitations from aortic insufficiency and advanced CAD
▪ Does not impede conduct of case
▪ Augments de-airing
▪ Catheter placement can be difficult
▪ Complex
Through conduits
▪ Allows antegrade protection of areas of CAD
▪ Obviates limitations from aortic insufficiency and advanced CAD
▪ Allows delivery without need to pressurize aortic root or interrupt surgery
▪ Requires conduits
▪ Complexity
▪ Right coronary distribution poor
Integrated
▪ More uniform distribution of cardioplegia
▪ Complexity
CAD, coronary artery disease.
Antegrade Cardioplegia
Advantages
Antegrade cardioplegia can be delivered through the aortic root, the coronary ostia or, the bypass conduits after the distal anastomosis have been completed. Antegrade cardioplegia has several advantages. Firstly, it mimics the natural mechanics of coronary flow through the myocardial microcirculation. Secondly, it is simple and can be accomplished with only a standard needle inserted into the aortic root, although specifically designed cardioplegia and cardioplegia-venting needle systems exist. Only in cases of significant aortic regurgitation or dissection of the ascending aorta is delivery by direct injection of the aortic root not feasible. In these cases the ascending aorta and/or the aortic valve is likely to be replaced at some point in the surgery, and an aortotomy to provide exposure and direct cannulation of the coronary ostia allows for the delivery of antegrade cardioplegia. Cardioplegia can be delivered either in an intermittent or in a continuous manner utilizing this approach through a variety of cannulas designed for the purpose.
Efficacy
Antegrade cardioplegia delivery may be inadequate in situations in which the coronary arterial circulation is severely diseased. This can either be due to large vessel disease or dysfunction of the microcirculation. In cases of severe multivessel coronary artery disease (CAD), proximal obstructive disease, such as left main stenosis and occluded primary coronary arteries, uniform distribution of cardioplegia may be impaired to the territories of myocardium supplied by those arteries. Additionally, the flow distribution of the coronary arterial microcirculation is altered by a number of pathologic processes, including atherosclerotic CAD and hypertension (15,16,17).
Limitations
Antegrade cardioplegia has several limitations. As mentioned earlier, aortic insufficiency can limit its feasibility. Although direct ostial cannulation can be used to overcome this limitation, some patients will have hemodynamically unimportant aortic insufficiency but impairment of the aortic valve to the degree that delivery of antegrade cardioplegia through the aortic root is not possible. If neither the aortic valve nor the ascending aorta is planned for replacement, access to the coronary ostia would require an aortotomy directly for this purpose, and the risk-benefit ratio of this maneuver would need to be assessed.
Direct cannulation of densely calcified coronary ostia is not without its own problems. Densely calcified ostia may require debridement to allow for cannulation, and this, or the cannulation itself, can result in the dislodgement or dissection of the tissue around the ostia.
Lifting or retraction of the heart for CABG or mitral valve procedures will distort the aortic valve to the point that it becomes incompetent. This is less of an issue with CABG in which the heart is frequently repositioned, and cardioplegia can be delivered when the heart is in a more normal anatomic orientation. During mitral valve surgery this is potentially more problematic, as the retraction must be released, antegrade cardioplegia delivered, and exposure to the mitral valve re-established. These maneuvers can interrupt and delay the conduct of the surgery.
Delivery through Bypass Grafts
Antegrade cardioplegia can be delivered through previously placed bypass grafts and then utilized as an adjunct to both root delivered antegrade and retrograde cardioplegia doses. Delivery of cardioplegia through bypass conduits offers several advantages. Firstly, cardioplegia is delivered to an area presumably underserved by antegrade coronary flow. Secondly, cardioplegia through bypass conduits is relatively nonobtrusive and can therefore be delivered either intermediately or continuously without disruption of the surgery. Finally, if pressure and flow monitoring are available, the delivery rate at a P.175
given flow can give an indication regarding the runoff and patency of the bypass graft.
Retrograde Cardioplegia
Advantages
Retrograde cardioplegia offers several distinct advantages. Firstly, it obviates the issues associated with antegrade cardioplegia and aortic insufficiency. Secondly, it provides distribution of cardioplegia independent of existing CAD. Thirdly, retrograde cardioplegia can be delivered without disrupting the conduct of the surgery. Even in situations in which the retrograde return of cardioplegia through the coronary artery ostia would potentially interfere with surgery (aortic valve surgery, proximal coronary artery bypass anastomosis), the judicious use of suction can allow for the continuation of surgery in a bloodless field. Conversely, cardioplegia can be briefly discontinued to allow for optimal exposure.
An additional benefit is that retrograde cardioplegia can be utilized for de-airing of the coronary arterial vasculature and the aortic root. At the completion of each distal anastomosis, retrograde cardioplegia is started, and before tying down the distal anastomotic sutures the vasculature can be allowed to de-air. This maneuver is relatively straightforward and removing air from the coronary arteries improves the delivery of subsequent doses of antegrade cardioplegia. Retrograde cardioplegia can also be utilized for more general de-airing before cross-clamp removal. Immediately before clamp removal, low potassium cardioplegia or even warm blood can be delivered in a retrograde manner, and this acts to augment other standard de-airing maneuvers.
With regard to myocardial protection, several studies have compared antegrade with retrograde cardioplegia. Jasinski et al. (18) randomized 158 patients undergoing CABG into two groups. Both groups received intermittent cold blood cardioplegia, but in one group cardioplegia was delivered in an antegrade manner and in the other in a retrograde manner. Cross-clamp times were longer and more cardioplegia was utilized in the group receiving retrograde cardioplegia, but no other significant operative differences were present between groups. The authors concluded that myocardial protection was superior in the retrograde group based on decreased ischemic events, inotrope use, and improved cardiac performance immediately after surgery. However, by 24 hours postoperatively, there was no difference in these parameters between groups.
Efficacy
The efficacy of retrograde cardioplegia is evidenced by the excellent results that it has afforded either alone or in conjunction with antegrade delivery of cardioplegia. Talwalkar obtained an operative mortality of 2% in a series of 100 patients operated on for valvular heart disease, either alone or in combination with CABG utilizing only retrograde cardioplegia (19,20).
Carrier et al. (21) were unable to demonstrate a benefit to retrograde cardioplegia. They analyzed the outcomes of 224 patients undergoing first time coronary artery bypass surgery who were randomized to antegrade versus retrograde blood cardioplegia. The authors found no significant difference in myocardial protection afforded by the two methods based on clinical outcomes (death, myocardial infarction) or cardiac enzyme release.
Retrograde cardioplegia alone (without antegrade cardioplegia doses) has been utilized as a strategy of myocardial protection in patients with valvular heart disease. Talwalkar et al. analyzed the outcomes of 100 consecutive patients who underwent surgery for valvular heart disease with retrograde cardioplegia alone for myocardial protection. Patients were ill [81% in New York Heart Association (NYHA) Class III or IV, 20% with left ventricular ejection fraction (LVEF) <40%] and underwent complex surgeries including redo-surgery (23%), concomitant CABG (24%), or ascending aortic aneurysm repair (8%). Despite the high-risk nature of the patient population, mortality was only 2% and no patients had a myocardial infarction. The authors concluded that good clinical outcomes could be obtained with retrograde cardioplegia alone (20).
These conflicting results from different studies are due in part to difficulty in isolating and defining the “key” variables associated with cardioplegia techniques. Even small alterations in technique, such as continuous versus intermittent delivery of cardioplegia through the same (retrograde) route, have been shown to be important. Louagie et al. (22) randomized 70 patients undergoing CABG to receive either intermittent or continuous retrograde blood cardioplegia. Left ventricular stroke work index was superior in the continuous cardioplegia group and the need for perioperative inotropic support was lessened. Additionally, the authors were able to demonstrate decreased levels of coronary sinus lactate and hypoxanthine with continuous cardioplegia and concluded that continuous cardioplegia provided superior myocardial protection.
The utility of retrograde cardioplegia in specific applications has been well studied. Borger et al. evaluated their experience with reoperative CABG and demonstrated that surgery without retrograde cardioplegia was an independent predictor of mortality (odds ratio, 2.8). The authors strongly recommended the use of retrograde cardioplegia in reoperative coronary artery bypass surgery (23).
Some authors have addressed the technical difficulties of antegrade cardioplegia delivery in reoperative patients by advocating the routine use of retrograde cardioplegia (23,24). A reduction in mortality has been associated with the use of retrograde cardioplegia in reoperative patients (23), highlighting the importance of adequate cardioplegia and optimal myocardial protection in reoperative coronary artery surgery outcomes. The improvement P.176
observed with retrograde cardioplegia may be due to the theoretical advantage of reduced emboli from diseased saphenous vein grafts (25) present in a high percentage of reoperative patients (26). Right ventricular protection can also be challenging in reoperative patients owing to frequently occluded native coronaries supplying the right ventricle. Retrograde cardioplegia does not completely resolve this potential problem because it is not uniformly delivered to the right ventricle and basal septum (27,28).
Retrograde cardioplegia has been advocated as a superior technique for myocardial protection in reoperative aortic valve procedures. Advantages of retrograde cardioplegia in this situation include the ability to perform valve replacement with limited interruptions for the delivery of cardioplegia through the coronary ostia, ability to deliver near-continuous cardioplegia, delivery of cardioplegia to areas of the myocardium with significant CAD, and obviate the need to manipulate the coronary ostia with perfusion cannulas (29). Additionally, in cases in which the patient has had a previous internal mammary artery placed, the option of performing the operation with continuous warm retrograde perfusion is available and avoids the need to control a previously placed internal mammary artery graft.
Limitations
Limitations of retrograde cardioplegia are not insignificant. Often retrograde catheters are difficult to place due to patient anatomy. If bicaval cannulation is being utilized, a small right-sided atriotomy can be utilized to overcome this obstacle. Additionally, if transesophageal echocardiography (TEE) is available, this can often be utilized to help guide retrograde catheter placement.
Optimal and uniform distribution of retrograde cardioplegia can be difficult to achieve. Although retrograde delivery of cardioplegia to the left ventricle is excellent, the septum and right ventricle are often underperfused. This problem of maldistribution is exacerbated by overly “deep” placement of the retrograde cannula and is due to the proximity of the right ventricular venous drainage to the coronary sinus ostia. This problem can be mitigated by the delivery of cardioplegia through right-sided vein grafts or through the right coronary ostia, if these options are available. Additionally, antegrade root doses of cardioplegia can be administered to provide right ventricle protection.
Care must be taken to avoid excess retrograde cardioplegia pressure. Our practice is to monitor retrograde pressure and aim for a goal of 20 to 35 mm Hg. Subjecting the cardiac venous systems to pressures in excess of 50 mm Hg has been shown to produce myocardial edema, hemorrhage, and myocardial injury (30).
One final note of caution with retrograde cardioplegia concerns the presence of a left-sided superior vena cava (SVC). This anomaly can be identified preoperatively on the long axis view of the echocardiogram as a dilated coronary sinus posterior to the left atrium. However, in the adult population, this is often “missed” due to its rare occurrence. An observant surgeon might suspect and look for a left SVC if an innominate vein is not seen during dissection for cannulation. A left SVC should be suspected if there is difficulty establishing arrest and if the right atrium seems to be unusually dilated. A left SVC to the coronary sinus continues to bathe the heart with “warm” (depending on the degree of systemic cooling employed) venous return, and difficulty maintaining an arrested and cold myocardium should trigger the consideration of this problem. Examination of the left side of the pericardium at the level of the pulmonary veins and left pulmonary artery should reveal the left SVC, which will cross over the anterior surface of the left pulmonary artery as it descends toward the roof of the left atrium. Control can be established either intrapericardially or extrapericardially. If the left internal mammary artery (LIMA) has previously been harvested and the left chest is open, extrapericardial control is also straightforward. Our preference is to place a small (16 French) vent into the left SVC with a purse string of 4-0 Prolene. A Rummel tourniquet is then placed more proximally to isolate the heart. It is then possible to deliver retrograde through a cannula in the coronary sinus ostium or directly into the left SVC. However, the coronary sinus ostia are often enlarged and may not seal well with a standard retrograde cannula. If a left SVC is present, inspection for presence or absence of an innominate vein should be undertaken. If no innominate vein is present, then sufficient drainage of the left SVC may be important to avoid venous congestion in the intracranial circulation.
Combined Antegrade and Retrograde Cardioplegia
The use of combined retrograde and antegrade cardioplegia allows the surgeon to capitalize on the advantages of each method and eliminate many of the shortcomings present when only one technique is used. Most frequently, antegrade and retrograde cardioplegia are delivered independently as the operative situation dictates. However, simultaneous delivery of both antegrade and retrograde cardioplegia appears to be safe. Initial concerns speculated that combined delivery of both antegrade and retrograde cardioplegia could result in high pressures within the cardiac vasculature and subsequent edema, hemorrhage, and myocardial injury. In fact, the simultaneous delivery of antegrade and retrograde cardioplegia may provide more homogeneous delivery of cardioplegia and superior myocardial protection compared with other techniques. One technique of simultaneous antegrade and retrograde delivery of cardioplegia involves the delivery of retrograde cardioplegia while antegrade cardioplegia is delivered through a completed bypass graft to the right side. The technique is designed to eliminate P.177
the potential for underperfusion of the right ventricle and septum that exists when only retrograde cardioplegia is delivered.
The potential superiority of combined retrograde and antegrade cardioplegia compared with antegrade cardioplegia alone has been evaluated in specific patient populations, with mixed results. Onorati et al. examined outcomes in 148 patients undergoing CABG for left main stenosis. Patients were retrospectively analyzed with respect to cardioplegia delivery route. Eighty-seven patients had antegrade cardioplegia alone whereas 61 patients received antegrade cardioplegia arrest followed by retrograde cardioplegia. Although most postoperative outcomes including mortality, postoperative myocardial infarction, and intra-aortic balloon pump (IABP) use were similar between groups, lower postoperative troponin levels and lower rates of atrial fibrillation were present in the patients with retrograde cardioplegia. The authors concluded that retrograde cardioplegia conveyed additional myocardial protection when compared with antegrade cardioplegia alone in this patient group (31).
Although an immense amount of literature comparing antegrade and retrograde cardioplegia exists, no single paper answers the question definitively for each situation and each patient subset. Our practice with adult patients has been to utilize antegrade cold blood cardioplegia in conjunction with retrograde cardioplegia whenever feasible. The advent of “microplegia” systems has enabled us to use large doses of near-continuous retrograde cardioplegia without introducing large volumes of crystalloid into the patient.
Cardioplegia Composition
A large variety of solutions have been utilized to arrest the heart and provide myocardial protection from ischemia and reperfusion. The agent most often utilized to provide cardiac arrest is potassium, most frequently in concentrations ranging from 10 to 40 mmol/L. Cardioplegia composition has been described as either “intracellular” (low sodium and calcium concentrations) or “extracellular” (higher concentrations of sodium, calcium, and the addition of magnesium). Additionally, cardioplegia can be divided into crystalloid cardioplegia and blood cardioplegia. To each of these subtypes, a host of additional electrolyte and pharmacologic agents can be added in various concentrations.
Crystalloid versus Blood Cardioplegia
Crystalloid cardioplegia, either intracellular or extracellular in composition, has been proved effective in a wide range of applications and has the benefits of low cost, simplicity of administration, and availability. Bicarbonate or other agents are typically added to provide buffering.
Blood cardioplegia offers several theoretical advantages over crystalloid cardioplegia, including the ability to carry oxygen, and excellent buffering capacity. Even with the addition of potassium for the initiation and maintenance of arrest, blood cardioplegia is similar in electrolyte and osmotic composition to blood which is what routinely perfuses the heart, and in particular the coronary vasculature. Additionally, blood has the potential to scavenge free radicals and minimize oxidative damage to the heart. With the advent of “microplegia” systems, large volumes of blood cardioplegia can be delivered with relatively minimal amounts of crystalloid being used. Microplegia is a cardioplegia technique that consists of mixing blood from the CPB circuit with small quantities of concentrated additives, potassium being the most frequently used. This technique relies on precision pumps to deliver accurate quantities of additives while minimizing the quantity of crystalloid within the cardioplegia solution. This in turn allows for the delivery of large quantities of continuous or intermittent cardioplegia without the “penalty” of large amounts of crystalloid being infused into the patient.
Although the oxygen-carrying capacity of blood made its addition to the cardioplegia solution attractive on theoretical grounds, results on the ability to alter myocardial oxygenation are mixed. Bjerrum et al. inserted small polarography catheters into the hearts of patients undergoing coronary bypass surgery. Patients were then randomized to receive either blood or crystalloid cardioplegia, and myocardial tissue oxygen saturations were obtained. The authors concluded that there were only “trivial” differences in myocardial tissue oxygen saturations between the patients receiving blood and those receiving crystalloid cardioplegia. The authors did note that by increasing the concentration of inhaled oxygen delivered during the case they were able to significantly increase myocardial oxygen concentrations (32).
Despite several studies demonstrating excellent outcomes with blood cardioplegia and the theoretical advantage that it might offer over crystalloid cardioplegia, it has been difficult to demonstrate the clinical superiority of blood cardioplegia. A study by Ovrum et al. randomized 1,440 consecutive patients undergoing coronary artery bypass surgery randomized to either cold crystalloid or cold blood cardioplegia. No difference was observed in outcomes, which included mortality, the use of inotropes and IABPs postoperatively, arrhythmias, or myocardial infarction. Additionally, the authors were unable to demonstrate a difference when only the high-risk patients were analyzed (33).
The “CABG Patch Trial” enrolled a cohort of high-risk patients (ejection fraction <35%) undergoing CABG. A retrospective analysis was carried out to determine the relative contribution that cardioplegia composition and delivery route had on morbidity and mortality. Operative P.178
mortality was lower (0.3% versus 2%, p = 0.02), myocardial infarctions were less frequent (2% versus 10%, p < 0.001), and shock was less common (7% versus 13%, p = 0.013) in the blood cardioplegia group. However, there was no difference in early (4% versus 6%) or late mortality (21% versus 24%) for the blood and crystalloid groups, respectively. Additionally, there was statistically less inotropic use, IABP use, and right ventricular dysfunction in those patients who received antegrade and retrograde cardioplegia compared with those that received antegrade cardioplegia alone, but no difference in survival between these two delivery methods could be demonstrated. The authors concluded that blood cardioplegia and combined antegrade and retrograde cardioplegia are superior to crystalloid and antegrade cardioplegia alone for the avoidance of perioperative morbidity, but that no short-term or long-term survival benefit was present (34).
Flameng described improved outcomes utilizing blood cardioplegia for heart valve surgery. After correcting for patient risk factors, he was able to demonstrate a significant advantage (relative risk, 0.44) associated with blood cardioplegia. The study was nonrandomized and had several limitations, including different delivery techniques (blood cardioplegia was delivered retrograde), dosing regimens (crystalloid cardioplegia was delivered as a single dose whereas blood cardioplegia was administered continuously), and the intervals over which the patients were operated on (crystalloid was employed earlier in the study) (35).
Guru et al. performed a meta-analysis comparing blood and crystalloid cardioplegia to determine which provided superior myocardial protection and improved postoperative outcomes. The authors searched for studies from 1965 to 2005 and included 35 studies comprising 5,044 patients. Although the treatment estimates for myocardial infarction (odds ratio, 0.78) and death (odds ratio, 0.80) favored blood cardioplegia, these differences were not statistically significant. The lack of statistically significant differences in death or myocardial infarction was not unexpected and was attributed to the low incidence of these outcomes and the relatively small sample size (36). However, the authors did note a significant reduction in the incidence of postoperative low-output syndrome (odds ratio, 0.54) and a reduction in postoperative myocardial enzyme release (odds ratio, -3.5 at 1 hour, -7.09 at 7 hours, -5.9 at 24 hours, -0.39 at 48 hours) associated with blood cardioplegia. The reduction in myocardial enzyme release was most prominent 7 hours postoperatively, and by 48 hours postoperatively was equivalent between the groups. This study has all the limitations inherent to meta-analysis, including heterogeneous patient populations, differences in surgical and cardioplegia techniques (temperature, route of delivery, etc.), and differing endpoints. Despite these limitations, this study provides some evidence to support the superiority of blood cardioplegia over crystalloid cardioplegia for myocardial protection. The clinical benefit of these differences is not clear (Table 3).
TABLE 3 Cardioplegia Vehicle
Technique
Pros
Cons
Crystalloid
▪ Inexpensive
▪ Simplicity
▪ Availability
▪ Large volume of crystalloid
▪ No buffering
▪ No oxygencarrying capacity
Blood
▪ Oxygen-carrying capacity
▪ Buffering capacity
▪ Similarity in electrolyte composition, osmolarity
▪ Free-radical scavenging ability
▪ Cost
▪ Complexity
Microplegia
▪ Large volume of cardioplegia but minimal crystalloid volume
▪ Accurate quantification of cardioplegia delivery
▪ Ability to further modify cardioplegia composition with additives
▪ Cost
▪ Complexity
Temperature
There is disagreement in the literature over the relative benefits of differing cardioplegia temperatures in regard to myocardial protection. Although the definition of “warm” cardioplegia (most commonly in the 34°C-35°C range) and “cold” cardioplegia (~4°C) are fairly consistent, the introduction of “tepid” cardioplegia or cardioplegia regimens that incorporate both warm and cold components adds additional complexity to the comparison. Although some studies have demonstrated the superiority of one cardioplegia temperature over another, other studies have been unable to demonstrate a difference. Some of the difficulties in reaching a definitive conclusion regarding the optimal cardioplegia temperature are that different patient populations may benefit from different cardioplegia regimens. The variability among studies in the composition, duration, and delivery route for cardioplegia administration makes comparisons between studies extremely difficult.
Despite the difficulties in isolating cardioplegia temperature as a variable, cold and warm blood cardioplegia have P.179
been compared in several distinct patient populations. Ascione et al. (37) evaluated the differences in myocardial protection afforded by warm and cold intermittent antegrade blood cardioplegia in patients with hypertrophic hearts undergoing aortic valve surgery. Left ventricular biopsies and postoperative troponin levels were used to quantify myocardial injury, and the authors reported less myocardial injury and less ischemic stress in patients receiving cold cardioplegia.
Cardioplegia temperature may also have extra-cardiac consequences. Martin et al. (38) reviewed 1,001 patients undergoing elective CABG with either warm or cold blood cardioplegia and found a significantly higher rate of neurologic events (4.5% versus 1.4%) and stroke (3.1% versus 1.0%) in those patients operated on utilizing warm blood cardioplegia. Rates of myocardial infarction, IABP utilization, and death were not significantly different between groups.
Conversely, the equivalence of warm and cold cardioplegia has been demonstrated as well. Franke et al. (39) compared intermittent antegrade cold and warm blood cardioplegia in a prospective randomized study of 200 patients undergoing elective CABG. Patient and operative characteristics were similar between the two groups and no difference in mortality, myocardial infarction, IABP use, or postoperative inotropic requirement was found. Patients receiving warm cardioplegia were less likely to require defibrillation following cross-clamp release, have less postoperative ventricular dysrhythmias, and they had a statistically significantly lower rate of reoperation for bleeding. Postoperative biochemical markers were lower in the patients who received warm cardioplegia, and the authors concluded that warm cardioplegia was effective and potentially provided superior myocardial protection compared with cold cardioplegia.
In a retrospective study by Mallidi and associates, warm or tepid blood cardioplegia was superior to cold blood cardioplegia in a cohort of 6,064 patients who underwent cardiac surgery. Patients receiving warm or tepid blood cardioplegia had lower rates of myocardial infarction, IABP use, low-output syndrome, and death in both the early and late postoperative periods (40). Limitations of this study include its retrospective nonrandomized nature and the fact that patients operated on in the more recent past had a higher rate of warm or tepid cardioplegia use.
Intermittent versus Continuous Cardioplegia
The theoretical advantage of continuous cardioplegia is obvious; that is, the heart is normally perfused in a continuous manner. Additionally, increases in myocardial acidosis have been noted between cardioplegia doses (41,42,43). Louagie randomized 70 patients undergoing CABG for three vessel CAD to receive either intermittent or continuous retrograde cold blood cardioplegia. Continuous cardioplegia was found to be superior in terms of postoperative left ventricular stroke work index. Additionally, patients in the continuous cardioplegia group were found to require less inotropic support and had lower levels of lactate and hypoxanthine in coronary sinus effluent following aortic unclamping. The authors concluded that continuous cardioplegia provided superior myocardial protection compared with intermittent cardioplegia (22) (Table 4).
TABLE 4 Cardioplegia Delivery Schedule
Technique
Pros
Cons
Intermittent
▪ Improved exposure
▪ Lower cardioplegia volume
▪ Increased inter-dose myocardial acidosis
Continuous
▪ Normal perfusion
▪ Increased postoperative LV performance
▪ Decreased inotrope requirement
▪ Operative field may not be “dry”
▪ Complexity
LV, left ventricular.
Additives
Nicorandil
Hyperpolarizing arrest mediated by potassium-containing cardioplegia solutions is the mainstay of most current cardioplegia regimens independent of mode of delivery, temperature, or additional modifications (Table 5) (44,45). Unfortunately, potassium is imperfect as an arresting agent and is in fact injurious (46) to the coronary vascular endothelium.
Numerous agents have been proposed to mitigate the deleterious effects of potassium-containing cardioplegia. Nicorandil, an adenosine triphosphate sensitive potassium (KATP) channel opener has been advocated for this role. Nicorandil is attractive for this application for several reasons. Firstly, by selectively opening the KATP channel, cardiac arrest can be achieved with reduced, and presumably less toxic, doses of potassium-containing cardioplegia. Secondly, nicorandil may protect against perioperative coronary vasospasm. Finally, nicorandil has been shown to act as a preconditioning agent and would provide additional myocardial protection by this mechanism (46).
Hayashi et al. attempted to determine the clinical utility of nicorandil-enhanced cardioplegia in 709 patients undergoing CABG. The patients were randomized to receive multiple doses of nicorandil or placebo during surgery. Nicorandil-treated patients required less cardioplegia to P.180
generate cardiac arrest, recovered spontaneous heart rhythm more frequently after aortic unclamping, and had less postoperative segmental S-T changes than controls. Additionally, patients treated with nicorandil had lower levels of malondialdehyde (a cardiac fatty acid-binding protein), creatine kinase myocardial band (CK-MB), and required lower doses of postoperative catecholamines. The authors concluded that the addition of nicorandil to potassium-containing cardioplegia solutions provided enhanced myocardial protection (46).
TABLE 5 Cardioplegia Additives
Technique
Pros
Cons
Nicorandil
▪ Less cardioplegia and potassium chloride requirement
▪ Reduced perioperative coronary spasm
▪ Preconditioning
▪ Reduced need for catecholamine use postoperatively
▪ Cost
L-arginine
▪ Decreased myocardial enzyme release
▪ Reduced postoperative cytokine levels
▪ Reduced pulmonary artery wedge pressure
▪ Cost
▪ Complexity
Insulin
▪ Increased survival and improved LV function in some studies
▪ Complexity
▪ Efficacy unclear
LV, left ventricular.
L-arginine
The critical role of the coronary microcirculation, and in particular the active role that the endothelial dysfunction (47) plays in ischemia-reperfusion injury, has generated interest in agents that could minimize endothelial dysfunction by protecting the coronary microcirculation. L-arginine, a nitric oxide (NO) donor, has been evaluated as a cardioplegia additive in an attempt to enhance myocardial protection. Carrier et al. (48) was able to demonstrate reduced myocardial enzyme release with the addition of L-arginine to cardioplegia. Colagrande et al. were able to demonstrate a reduction in postoperative myocardial enzyme release and postoperative cytokine levels in patients who received L-arginine-supplemented cardioplegia (49). Lower postoperative pulmonary artery wedge pressures were preset in patients treated with L-arginine, but no statistically significant differences in cardiac performances were present on echocardiographic assessment.
Insulin
Insulin has been evaluated as an adjunct to cardioplegia in an attempt to improve myocardial protection. Infusion of glucose-insulin-potassium solutions to mitigate the electrocardiographic changes associated with myocardial infarction was first described more than 40 years ago (50). Since that time several small nonrandomized trials have demonstrated improved survival (31,51) utilizing cardioplegia solutions containing insulin, the Insulin Cardioplegia Trial was designed to confirm the additional benefits that insulin-augmented cardioplegia solutions provided with respect to myocardial protection. Rao et al. performed a prospective randomized trial of 1,127 patients undergoing CABG for unstable angina. No differences were found between patients receiving standard cardioplegia solutions and insulin-enhanced cardioplegia with respect to postoperative myocardial infarction, IABP use, low-output state, and mortality. The authors concluded that insulin-enhanced cardioplegia did not provide superior myocardial protection for this patient population (52).
Monitoring
Various myocardial monitoring techniques have been utilized to evaluate and optimize the uniformity and effectiveness of cardioplegia delivery with regard to both temperature and pH (Table 6). The goal of these monitoring techniques is to provide additional safety and ensure adequate myocardial protection for patients undergoing cardiac surgery. Because cardioplegia delivery is heterogeneous, especially in patients with severe CAD and when utilizing retrograde cardioplegia, a methodology to ensure adequate cardioplegia distribution offers the promise of improved outcomes.
Temperature
Temperature measurement using one or more thermocouple needles inserted into the myocardium is the most commonly used intraoperative monitoring technique. P.181
Typically, a single needle is utilized and is inserted into the septum. By following the temperature as cardioplegia is delivered, myocardial cooling can be followed and an appropriate cardioplegia dose delivered. The interval between cardioplegia doses can also be altered by watching myocardial temperature rise between cardioplegia doses, and then redosing when appropriate. Finally, temperature response can be utilized to assess the effectiveness of cardioplegia delivery in cases of aortic insufficiency and to determine if retrograde cardioplegia is being delivered through an appropriately positioned cannula.
TABLE 6 Myocardial Monitoring Techniques
Technique
Pros
Cons
Temperature
▪ Ease of use
▪ Location dependent
▪ Temperature is not equivalent to protection
pH
▪ Potential to alter surgical conduct and improve protection and outcomes
▪ Specialized equipment
▪ Efficacy unclear
Myocardial pH
Myocardial pH monitoring is not as widely utilized as temperature monitoring, but provides an opportunity for even more information on the myocardium during aortic cross-clamping. Measurement of myocardial pH can be accomplished by either measurement of coronary sinus blood effluent or by direct myocardial pH measurement through small pH meters inserted directly into the myocardium.
Graffigna et al. (41) evaluated the utility of pH monitoring in 19 patients undergoing cardiac surgery, utilizing samples of coronary sinus blood. Changes in myocardial pH, PO2, and PCO2 were monitored while intermittent doses of intermittent warm blood cardioplegia were administered antegrade or retrograde every 15 minutes. A decrease in myocardial pH was noted following each dose of cardioplegia, and pH became progressively more acidotic during each additional cycle of ischemia following cardioplegia administration. The authors concluded that myocardial ischemia is not fully reversed by cardioplegia administration and that during protracted aortic cross-clamp episodes pH monitoring could help guide cardioplegia administration.
Khuri et al. (42) has evaluated the utility of myocardial pH as both a predictor of postoperative inotrope use (43) and long-term survival (42) following cardiac surgery. In both studies, myocardial pH was measured with a small electrode that was placed in the myocardium during surgery. Monitoring not only had the ability to predict outcomes based on low pH values but also had the potential to alter the conduct of surgery to change outcomes.
ADDITIONAL STRATEGIES TO ENHANCE MYOCARDIAL PROTECTION
The Role of Anesthetic Agents in Myocardial Protection
Volatile anesthetic agents have been employed routinely for cardiovascular anesthesia. In addition to the anesthetic effects, volatile anesthetic agents provide some degree of cardioprotection as well. The precise mechanism by which volatile anesthetics provide myocardial protection is complex and appears to be multifactorial. It appears that volatile anesthetics ameliorate the deleterious effects of reactive oxygen species on the myocardium during ischemia reperfusion. Additionally, volatile anesthetic agents appear to modulate activity of the KATP channels in both the mitochondria and sarcolemma. The precise mechanism by which KATP channel modulation produces preconditioning remains controversial (53).
In addition to the early protection (minutes) afforded by ischemic preconditioning, a late period of protection (48-72 hours) exists as well (54). This delayed preconditioning phenomenon has been observed with volatile anesthetics as well. Tanaka et al. (55,56) demonstrated that isoflurane administration 24 hours before prolonged myocardial ischemia in rabbit hearts provided myocardial protection and reduced infarct size.
Clinical evidence for the protective effects of volatile anesthetics exists as well. Julier et al. conducted a prospective randomized trial in patients undergoing CABG and was able to demonstrate a reduction in N-terminal brain natriuretic peptide with the use of sevoflurane (57). No difference in postoperative troponin release was noted.
However, other studies have demonstrated a reduction in myocardial enzyme leakage following preconditioning with volatile anesthetics (58). Improved ventricular performance has also been achieved with inhalational preconditioning strategies utilizing isoflurane (59) and sevoflurane (60,61). The clinical utility and magnitude of myocardial protection achieved with volatile anesthetics for cardiac surgery is still evolving. Currently, most patients undergoing cardiac surgery receives volatile anesthetics during some interval of their cardiac surgery, but until the optimal agent, dose, and timing of administration are further defined, the benefit of volatile anesthetics for myocardial protection will remain unclear.
Acute Normovolemic Hemodilution
The benefits of avoiding blood transfusions in patients undergoing cardiac surgery have become generally accepted and this has led to multiple strategies to limit transfusion. One of these strategies, acute normovolemic hemodilution (ANH), has been shown to provide myocardial protection in patients undergoing coronary artery bypass. Licker et al. randomized 84 patients undergoing CABG and utilized antegrade cold blood cardioplegia, and the experimental group underwent ANH to a goal hematocrit of 28%. The patients who received ANH experienced less myocardial injury as evidenced by significantly lower postoperative serum levels of troponin I and myocardial fraction of CK-MB. Additionally, patients receiving ANH had lower inotropic requirements and lower rates P.182
of atrial fibrillation or conduction block postoperatively. The authors postulate that the primary mechanism of myocardial protection is related to improved rheologic characteristics present at a lower hematocrit, and that this reduction in viscosity provides advantages to myocardial blood flow, especially to underserved areas of the myocardium (62).
Neutrophil Depletion or Inactivation
The significant contribution of neutrophils to reperfusion injury has been generally accepted (63,64,65,66). Neutrophils are activated during CPB, accumulate in the microvasculature, and subsequently migrate out of the vasculature. Neutrophils then cause tissue injury by the release of enzymes, reactive oxygen species, and other toxic substances. Strategies that minimize the destructive effects of neutrophils on the myocardium have the potential to reduce myocardial injury associated with cardiac surgery.
One strategy to reduce neutrophil injury to the myocardium is neutrophil filtration, either in the CPB circuit or from the cardioplegia circuit. Palatianos et al. randomized 160 patients undergoing CABG and removed the neutrophils and platelets from the cold blood cardioplegia. Treated patients experienced lower rates of postbypass ventricular fibrillation, needed less attempts at defibrillation, had lower postoperative inotropic requirements, and had lower serum levels of cardiac enzymes postoperatively compared with patients who did not have filtration of their cardioplegia (67).
TABLE 7 Intraoperative Adjuncts for Myocardial Protection
Technique
Pros
Cons
Anesthetic agents
▪ Ameliorate deleterious effects of reactive oxygen species
▪ Provide preconditioning
▪ Unclear which agents are best
Acute normovolemic hemodilution
▪ Less myocardial injury, CK-MB release, and decreased inotrope requirement
▪ Reduced incidence of atrial fibrillation and conduction block
▪ Efficacy not demonstrated in all patient groups
▪ Some patients are too anemic for this technique
Neutrophil depletion
▪ Decreased postbypass ventricular fibrillation
▪ Lower inotrope use and lower postoperative cardiac enzyme release
▪ Cost
▪ Complexity
Erythropoietin
▪ Limits myocardial injury
▪ Cost
N-acetylcysteine
▪ May reduce oxidative stress
▪ May interfere with preconditioning
▪ Cost
▪ Complexity
Deferoxamine
▪ Decreased lipid peroxidation
▪ Increased myocardial protection, LVEF
▪ Decreased postoperative wall motion abnormalities
▪ Cost
▪ Complexity
▪ Not proved in large studies
Statins
▪ Increased nitric oxide release
▪ Anti-inflammatory properties
▪ Antioxidative properties
▪ Decreased monocyte adhesion
CK-MB, creatine kinase myocardial band; LVEF, left ventricular ejection fraction.
Noncardioplegia Medications
Erythropoietin
The clinical use of recombinant erythropoietin has become widespread as therapy to enhance erythrocyte production (Table 7). Erythropoietin is the primary growth factor that controls erythroid precursor survival and subsequent red blood cell production. It is commonly used in patients with depressed bone marrow and those with inadequate autologous erythropoietin production. More recently, it has been recognized that erythropoietin has antiapoptotic effects and this has sparked interest in the use of erythropoietin as an agent to mitigate organ injury.
Erythropoietin has been shown to protect myocytes from hypoxia and oxidative stress and has been shown P.183
to limit myocardial injury in animal models of ischemia reperfusion (68). Currently the clinical utility of erythropoietin for myocardial protection is under evolution.
N-acetylcysteine
Pharmacologic agents to scavenge reactive oxygen species (“free-radical scavengers”) have been utilized to minimize myocardial injury associated with ischemia reperfusion (69). Fischer et al. administered N-acetylcysteine (NAC), a reactive oxygen species scavenger, to patients undergoing CABG. Myocardial injury was evaluated by obtaining ventricular biopsies. Myocardial tissue was assayed for the enzymes caspase-3 and caspase-7, which are central to the apoptosis pathway. Patients treated with NAC had significantly lower levels of both caspase-3 and caspase-7. However, no differences in clinical outcome variables, including postoperative left ventricular function, inotropic requirement, or cardiac index, were detected, and there were no deaths or myocardial infarctions in either group. The relatively small sample size in this study may be responsible for the lack of clinical differences between groups despite the immunohistochemical differences present in the myocardium.
A recent randomized, double-blind, placebo-controlled trial of 100 patients undergoing operative myocardial revascularization with or without perioperative NAC was performed by El-Hamamsy et al. of the Montreal Heart Institute (70). Patients were evaluated for both clinical data (death, myocardial infarction, low-output syndromes, arrhythmias, bleeding, transfusion requirements, and intensive care unit and hospital lengths of stay) and biochemical markers (CK-MB, troponin T, interleukin-6, creatinine, hemoglobin, and platelet levels) postoperatively. There were no significant differences between the two groups with regard to the clinical outcomes or biochemical markers. The authors concluded that the prophylactic use of NAC in patients undergoing CABG surgery does not lead to improvements in clinical outcomes or biochemical markers.
Deferoxamine
Deferoxamine is an iron chelator that reduces myocardial injury by reducing the amount of hydroxyl radical formation generated by iron-catalyzed Fenton reactions. Deferoxamine has been shown to reduce lipid peroxidation and improve myocardial protection after CABG. Paraskevaidis randomized 45 patients undergoing CABG to receive either deferoxamine or placebo. Patients were evaluated for lipid peroxidation by measuring thiobarbituric acid reactive substances postoperatively. Patients were also evaluated with echocardiography immediately postoperatively and at 1 year to assess myocardial performance. The authors were able to demonstrate that deferoxamine treatment resulted in a reduction in lipid peroxidation as measured by thiobarbituric acid reactive substances. Additionally, treatment with deferoxamine was associated with a statistically significant improvement in ventricular performance (increased ejection fraction, decreased segmental wall motion abnormalities) in both the immediate postoperative period and at 1-year follow-up (71).
Statins
Statins (HMG-CoA reductase inhibitors) have been widely employed to reduce serum cholesterol levels in patients. As more experience has been gained with the multiple effects of statins, it has become apparent that they also convey some degree of myocardial protection from ischemic injury. The mechanism of action is multifactorial; one mechanism involves increased NO production at the level of the vascular endothelium. Additionally, statins reduce monocyte adhesion and have both anti-inflammatory and antioxidant properties. The protective effect of statins has been demonstrated in animal models of myocardial ischemia reperfusion, in the setting of percutaneous coronary interventions, and in CABG (72).
Ischemic Preconditioning
Ischemic preconditioning is the phenomenon in which an initial sublethal ischemic injury conveys protection against subsequent ischemic insults. Because adenosine triphosphate (ATP) repletion following brief episodes of ischemia occurs slowly (73), it was initially assumed that repeated episodes of ischemia reperfusion would result in a progressively more severe myocardial injury.
Murry et al. discovered that repeated brief episodes of ischemia led to a subsequent reduction in infarct volume following additional periods of prolonged regional coronary ischemia in a canine model. They developed the concept of preconditioning with ischemia that has been reproduced in both animal and human models (74,75,76,77). Although the mechanisms for ischemic preconditioning have not been completely elucidated, several molecular targets involved in the protective mechanism have been identified, including isoforms of protein kinase C, tyrosine kinase, and NO (78,79,80). Emerging research suggests that the mechanisms responsible for fetal heart tolerance to ischemic stress may be involved in similar mechanisms in the adult. Studies in neonates have shown that protein kinase Cε (PKCε) upregulation and KATP channel endogenous activation may play a role in tolerance to ischemic stress (81,82,83).
Recent studies of ischemic preconditioning have been performed in patients undergoing cardiac surgery. Ghosh et al. randomized 120 patients into three groups: (a) group I had CPB with intermittent cross-clamp P.184
fibrillation; (b) group II had CPB with cardioplegic arrest using cold blood cardioplegia; and (c) group III had surgery on the beating heart (off-pump surgery). Patients were randomly divided within groups to control and preconditioning subgroups (one cycle of 5 minutes of ischemia/5 minutes reperfusion before intervention). Ischemic preconditioning was induced by clamping the ascending aorta in groups I and II, or by clamping the coronary artery in group III. Biochemical and clinical variables were assessed perioperatively. There were no perioperative myocardial infarctions or deaths in any groups. Total release of troponin T in groups I and II (both groups undergoing surgery with CPB) was not different with or without ischemic preconditioning. In contrast, total troponin T release was significantly reduced by ischemic preconditioning in group III during the first 48 hours. The authors concluded that ischemic preconditioning may afford improvements in myocardial protection in off-pump cardiac surgery; however, it may not offer any additional benefit in patients undergoing on-pump cardiac surgery (84).
Future studies in pharmacologic manipulation of these genes and biochemical pathways may further elucidate the precise mechanism of myocardial preconditioning and provide clinically relevant myocardial protection.
Fibrillation
Although cardioplegia in its various iterations is currently the most commonly employed strategy for myocardial protection (44,45), the simplicity and excellent clinical results obtained with fibrillatory arrest, with or without intermittent aortic cross-clamping, make this technique attractive in certain applications. Until the mid 1970s, intermittent fibrillation with aortic cross-clamp (noncardioplegic technique) coupled with various degrees of systemic hypothermia was the dominant strategy for myocardial protection. Fibrillatory techniques obviate many of the maneuvers required for optimal cardioplegia delivery in patients undergoing reoperative coronary artery surgery. It does not require isolation and control of a previously placed and patent LIMA to left anterior descending (LAD) graft, and thereby avoids possible injury. It circumvents problems related to cardioplegia delivery, which is often difficult in the setting of reoperative CABG.
Intermittent fibrillation relies on the principle of ischemic preconditioning. Ischemic preconditioning is the phenomenon in which brief periods of ischemia render the target organ resistant to subsequent episodes of ischemia (85). Ischemic preconditioning is thought to play a role in the myocardial protection achieved with intermittent fibrillation and aortic cross-clamp technique. The protective effects of short intervals of ischemia have been related to the adenosine receptor, multiple kinase, and alterations in the KATP channel (86,87,88). Studies utilizing adenosine, adenosine agonist, and KATP channel openers to mimic ischemia-produced myocardial protection through pharmacologic preconditioning have produced mixed results (89).
Few studies have directly analyzed the results of CABG using intermittent fibrillation and aortic cross-clamping. Flameng concluded that both techniques offer “good” myocardial protection but that cardioplegia prevented the onset of ischemia-induced deterioration in cardiac metabolism (35). Other authors have compared cardioplegic with noncardioplegic techniques and concluded that cardioplegia offered superior results; however, these studies were neither randomized nor prospective (13).
Excellent clinical results have been achieved using hypothermic fibrillatory technique for CABG. Akins reported on 1,000 consecutive patients utilizing this technique, with a very low mortality of 0.4%. Additionally, major morbidity was low with a 0.7% incidence of permanent neurologic injury and an incidence of perioperative myocardial infarction of 1.8%. Aortic cross-clamping was not utilized in this series (90). Bonchek et al. reported similar excellent results using noncardioplegic technique for CABG in a group of 3,000 “high-risk” patients (91). Reoperative patients were excluded from this study.
Reoperative coronary artery surgery incurs higher rates of mortality, perioperative myocardial infarction, and low-output syndrome when compared with primary surgery (24,92,93,94). Yau reported a mortality of 6.3% in a group of patients undergoing reoperative CABG from 1992 to 1997 (24). Stephan et al. reported operative mortality for reoperative coronary surgery of 7.3% (95), and similar results have been reported by others (26,96). Shimada et al. reported on a series of 200 consecutive patients undergoing reoperative coronary surgery, with a morality of only 2.5% (97).
Cardioplegia delivery is more difficult in reoperative coronary artery surgery for many reasons; reoperative patients often have more advanced native vessel disease at the time of their reoperative surgery (24). Diseased, atherosclerotic vein grafts are often difficult to safely utilize for the delivery of cardioplegia. As the use of LIMA as a bypass conduit has become more common, it has added to the complexity of reoperative cardiac surgery. In reoperative surgeries in which the LIMA has been utilized, the LIMA pedicle must be dissected free, controlled, and an alternative method of cardioplegia delivery to the LAD territory (i.e., retrograde cardioplegia) must be utilized. Additionally, dissection of the LIMA pedicle may result in injury to the graft and jeopardize the vascular supply to the LAD territory (98).
Intermittent fibrillation with or without aortic cross-clamping represents a viable, although currently infrequently used, strategy for myocardial protection in these patient groups. This technique should be considered as an alternative to cardioplegia-based protection strategies in some circumstances.
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MYOCARDIAL PROTECTION FOR OFF-PUMP REVASCULARIZATION
Concern for myocardial protection during off-pump coronary artery bypass (OPCAB) stems from the understanding that the brief periods of coronary occlusion necessary to visualize the target vessels during construction of distal anastomosis cause regional ischemia. This can result in myocardial injury that may not only affect the ischemic region, but also may cause accumulated global dysfunction after sequential occlusions imposed during multivessel bypass grafting. In animal models of simulated OPCAB, even brief periods of ischemia lead to contractile dysfunction, endothelial injury in the target vessel, and apoptosis that contributes to post revascularization pathology. Strategies for protecting the myocardium from ischemic and reperfusion injury have therefore been developed to improve acute and potentially longer-term outcomes following OPCAB procedures.
Myocardial protection during OPCAB has evolved because techniques for performing the procedure have been refined (Table 8). Before the development of suction-based stabilizers, intermittent pharmacologic arrest and profound bradycardia were induced during the procedure with adenosine and short-acting β-blockers. In addition to reducing motion of the target vessel, this strategy achieved some degree of myocardial protection by reducing myocardial oxygen demand. These maneuvers have largely been abandoned in common clinical practice, with the widespread application of second- and third-generation suction-based coronary stabilizers.
Ischemic preconditioning has also enjoyed brief popularity as a cardioprotective strategy during OPCAB. The theoretical benefit of brief occlusion and reperfusion before the long occlusion period necessary to construct a coronary anastomosis was supported by abundant laboratory evidence showing improved myocardial protection in the region served by the occluded coronary artery. Ischemic preconditioning has not been universally shown to attenuate myocardial contractile dysfunction or stunning, and its clinical use in OPCAB has been questioned. As the number of bypass grafts routinely performed during off-pump cases has increased, the enthusiasm of surgeons for performing repeated episodes of ischemic preconditioning for each coronary artery has diminished.
TABLE 8 Myocardial Protection without Cardioplegia
Technique
Pro
Con
Ischemic preconditioning
▪ Decreased total troponin T in studies of coronary clamping
▪ Requires multiple aortic clamps
Fibrillation
▪ Obviates need for cardioplegia
▪ Simplicity
▪ Does not require LIMA control in redo surgeries
▪ Repeated aortic clamping
▪ Anastomotic time limited
Off-pump surgery
▪ Avoidance of cardiopulmonary bypass and sequelae
▪ Technical challenge
▪ Unclear which patient groups derive maximal benefit
LIMA, left internal mammary artery.
A number of other myocardial protection strategies developed early in the experience of OPCAB remain in routine use. Maintenance of adequate systemic blood pressure by optimizing preload conditions and the use of vasopressors is part of careful anesthetic management. During target vessel occlusion, however, this practice is an important component of myocardial protection because perfusion to ischemic myocardium through collaterals is dependent on this perfusion pressure.
Another myocardial protection strategy that may be taken for granted is the careful use of traction sutures, apical heart positioners, and coronary stabilizers that provide adequate exposure of the target vessel without excessively compressing the cardiac chambers and avoiding undue hemodynamic compromise. When ideally placed, these devices do not interfere with the cardiac cycle, vasopressor requirements are minimized, and overall myocardial oxygen demand is minimized. This careful positioning of the heart should be considered a routine strategy for myocardial protection. Finally, thoughtful selection of the order in which distal anastomoses are constructed during a multivessel OPCAB procedure can limit the degree of regional ischemia to which the heart is subjected. Occlusion of the most highly collateralized target vessel first allows this territory to be perfused through collaterals during construction of the anastomosis. Subsequently, occluded territories can then be perfused through reversed flow in the collaterals through completed grafts.
Construction of one or more proximal anastomoses early in the operative sequence is an adjunct to the thoughtful selection of the order in which distal anastomoses are constructed. Construction of a proximal anastomosis before the first distal anastomosis allows immediate reperfusion of the ischemic territory after completion of the distal anastomosis. If this target vessel is collateralized, then a subsequently constructed distal anastomosis to the collateralizing target vessel can be performed with the benefit of reversed collateral flow originating from the first bypass graft. An advantage of grafting the LAD with an in situ LIMA pedicle first in the operative sequence is that this anastomosis requires minimal lifting of the heart, and subsequent target vessels can be exposed and grafted with the benefit of collateral P.186
flow from the LIMA-to-LAD anastomosis without the need to perform a proximal anastomosis.
An intracoronary shunt may be placed if significant hemodynamic compromise occurs after target vessel occlusion despite use of the routine measures described in the preceding text. The shunts (ClearView Intracoronary Shunts; Medtronic, Inc.) range in size from 1.0 mm to 3.0 mm. When appropriately sized for the target vessel, they are easily placed and removed and provide significant flow and a near-bloodless field. Intracoronary shunts may be particularly useful with large right coronary arteries to avoid bradyarrhythmias, intramyocardial vessels in which placement of an occlusive vessel loop may be hazardous, and critical anatomy in which occlusion of an important collateralizing vessel may lead to global myocardial ischemia and hemodynamic collapse. The shunt is removed and the coronary artery is de-aired before tying the suture on the distal anastomosis and flow is re-established.
With experience and gentle application of the principles described, the vast majority of patients tolerate OPCAB grafting of all coronary targets. However, the cumulative effect of sequential coronary occlusions can occasionally lead to a downward spiral of hemodynamics. At times, it may be helpful to provide accessory perfusion to the myocardium while other vessels are occluded. Perfusion-assisted direct coronary artery bypass (PADCAB) directly perfuses myocardium supplied by a bypassed coronary artery by providing a controlled flow down the conduit. Inflow to the circuit and pump is provided by a catheter placed in the ascending aorta or femoral artery. Use of a computer-controlled blood delivery system (Quest Medical myocardial protection system [MPS]; Quest Medical, Allen, TX) allows for exact control of coronary perfusion pressure. Pharmacologic additives and temperature control may accentuate its protective effects. Unlike other protective strategies, including proximals-first grafting and shunts, the coronary perfusion pressure with PADCAB is independent of systemic pressure. This technique is especially helpful with collateralized targets because coronary flow can be driven through collaterals with suprasystemic pressure to supply adjacent myocardium. One can also measure and document graft patency and flows through the circuit. Multiple grafts can be perfused simultaneously with the use of a multilimbed perfusion set. It is important not to discontinue flow through all grafts simultaneously when proximal anastomoses are performed. Each conduit should be disconnected from the multilimbed perfusion set separately to perform its proximal anastomosis. We use PADCAB selectively to minimize regional ischemia and improve myocardial protection in cases of critical coronary anastomosis and profound cardiac dysfunction. PADCAB may also be used more liberally early in a surgeon's OPCAB experience to optimize hemodynamics and broaden the application of OPCAB.
Although it is not strictly a form of myocardial protection, IABP counterpulsation is a form of circulatory support that effectively preserves hemodynamics during OPCAB surgery for patients who are marginal candidates for the procedure. Patients at high risk for OPCAB failure due to severe proximal multivessel CAD, recent myocardial infarction, and severe ventricular dysfunction, and who also have comorbid disease that makes the avoidance of CPB desirable, are candidates for this support. The IABP improves hemodynamic stability and virtually eliminates the need for inotropic support during exposure and occlusion of target vessels in this challenging subpopulation of patients. This strategy thereby allows surgeons to safely extend the benefits of OPCAB surgery to high-risk patients who would otherwise be marginal candidates for the procedure.
CONCLUSION
Many techniques are available for the provision of myocardial protection, each with its particular strengths and weaknesses. The continued refinement and evolution of existing techniques as well as the development of new strategies of myocardial protection emphasize that there is no one best technique for all patients and all clinical situations. Appropriate choice of a protection strategy must take into consideration physician and institutional experience as well as patient factors.
KEY POINTS
Optimal strategies for myocardial protection are dependent on patient population, disease process, and institution. Trade-offs exist between efficacy, cost, and complexity. Strategies for myocardial protection should be developed within this context. One size does not fit all.
Myocardial protection encompasses more than just cardioplegia. Anesthetic agents, CPB, surgical techniques, and pre- and postoperative care, all affect the ability of the myocardium to tolerate cardiac surgery.
Because most techniques provide at least adequate myocardial protection, patient survival may not be a sensitive outcome measure to assess different myocardial protection techniques. More sophisticated measures of myocardial performance following surgery may be a better method to evaluate the difference in myocardial protection. Additional clinical outcome measures, such as postoperative inotrope and IABP use, may be useful.
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Preservation of myocardial function during the ischemic period, that is, during the period in which the aorta is cross-clamped, is best achieved by putting the heart into a state of hibernation using a solution – generically termed “cardioplegia.” The purpose of cardioplegia is to cause rapid diastolic cardiac arrest. This produces a still, flaccid heart, which facilitates surgery and also is the state in which myocardial metabolism is almost at its lowest levels. Further reduction in the metabolic state of the heart is achieved by cooling using cold cardioplegia and also by core/ cooling of the body.
Over the past 50 years, many therapeutic strategies have been developed to protect the heart during surgery (Table 15-1). This concept of shielding the heart from perioperative insult originated in 1950 with the review article by Bigelow and colleagues in which hypothermia was reported “as a form of anesthetic” that could be used to expand the scope of surgerysurgery. It was proposed that hypothermia could be used as “a technique that might permit surgeons to operate on the bloodless heart without recourse to extracorporeal pumps and perhaps allotransplantation of organs.” Five years later, Melrose and colleagues reported another way to stop and restart the heart reliably by injecting potassium citrate into the root of the aorta at both normal and reduced body temperatures. 3 Soon thereafter, the clinical application of potassium citrate arrest was adopted by many centers. Interest in using the Melrose technique waned, however, with subsequent reports that potassium citrate arrest was associated with myocardial injury and necrosis. Within a short time, many cardiac surgeons shifted from using potassiuminduced arrest to normothermic cardiac ischemia (i.e., normothermic heart surgery performed with the aorta occluded while the patient was on cardiopulmonary bypass), intermittent aortic occlusion, or coronary artery perfusion. Experimental and clinical evidence showed, however, that normothermic cardiac ischemia was associated with metabolic acidosis, hypotension, and low cardiac output.4–6
As a consequence, there was a renewed interest in discovering ways to arrest the heart. Bretschneider published the principle of arresting the heart with a low-sodium, calciumfree solution.7 It was Hearse and colleagues, however, who studied the various components of cardioplegic solutions, which led to the development and use of St. Thomas solution. 8 The components of this crystalloid solution were based on Ringer’s solution with its normal concentrations of sodium and calcium with the addition of potassium chloride (16 mmol/L) and magnesium chloride (16 mmol/L) to arrest the heart instantly. The latter component was shown byHearse to provide an additional ardioprotective benefit. In 1975, Braimbridge and colleagues introduced this crystalloid solution into clinical practice at St. Thomas Hospital.9 Gay and Ebert showed xperimentally that lower concentrations of potassium chloride could achieve the same degree of chemical arrest and myocardial protection afforded by the Melrose solution without the associated myocardial necrosis reported earlier.10 Shortly thereafter, Roe and colleagues reported an operative mortality of 5.4% for patients who underwent cardiac surgery with potassiuminduced arrest as the primary form of myocardial protection. 1 In 1977, Tyers and colleagues reported that potassium cardioplegia provided satisfactory protection in over 100 consecutive cardiac patients.12 By the 1980s, normothermic aortic occlusion had been replaced for the most part by cardioplegia to protect the
heart during cardiac surgery. The major controversy at the time (and one that persists today) was not whether cardioplegic solutions should be used, but what were the ideal
components of those solutions. The chief variants consisted of (1) the Bretschneider solution, consisting primarily of sodium, magnesium, and procaine, (2) the St. Thomas solution, consisting of potassium, magnesium, and procaine added to Ringer’s solution, and (3) potassium-enriched solutions containing no magnesium or procaine (Table 15-2).
Coincident with this controversy, another variant of cardioplegia was introduced, that of using potassium-enriched blood cardioplegia.13,14 The theory was that blood would be superior delivery vehicle based on its oxygenating and buffering capacity. Ironically,Melrose and colleagues initially used blood as the vehicle to deliver high concentrations of potassium citrate more than 20 years earlier. While hypothermia and potassium infusions remain the cornerstone of myocardial protection during on-pump heart surgery, many other cardioprotective techniques and methodologies are available.3,15 Although many of these techniques have been reported to confer superior protection and improve patient outcomes, the ideal cardioprotective technique, solution, and method of administration have yet to be found. Fortunately, the majority of cardioprotective strategies now available do allow patients to undergo conventional and complex heart operations with an operative mortality rate ranging from less than 2 to 4%.
The term myocardial protection refers to strategies and methodologies used either to attenuate or to prevent postischemic myocardial dysfunction that occurs during and after heart surgery. Postischemic myocardial dysfunction is attributable, in part, to a phenomenon known as ischemia-reperfusion-induced injury. Clinically, it manifests by low cardiac output and hypotension and may be subdivided into two subgroups: eversible injury and irreversible injury. The two typically are differentiated by the presence of lectrocardiographic abnormalities, elevations in the levels of specific plasma enzymes or proteins such as creatine kinase and troponin I or T, and/or the presence of regional or global echocardiographic wall motion abnormalities. With respect to coronary artery bypass grafting (CABG) alone, 10% of patients may experience myocardial infarction (MI), severe ventricular dysfunction, heart failure, and/or death despite advances in surgical technique. The impact from these complications both on families and on society is enormous. From an economic standpoint, the initial hospital cost of CABG is approximately $10 billion annually; it is likely, then, that complications after CABG consume an additional $2 billion in U.S. health care resources each year.1 The purpose of this chapter is to review the history of myocardial protection, to update the reader regarding the current protective techniques, to examine the mechanisms underlying ischemiareperfusion injury, and to discuss several new strategies currently under investigation.
The principal determinants of myocardial energy utilization are left ventricular enddiastolic wall tension (LVEDP) and electromechanical activity; limitation of both of these parameters can thus limit myocardial metabolic demand.During diastole, with low LVEDP, myocardial oxygen consumption and energy ubstrate
utilization is minimized. The rapid attainment of diastolic cardiac arrest at the onset of the ischemic period following application of the aortic cross-clamp effctively places the heart in a state of hibernation, particularly if the myocardium is simultaneously cooled. Electromechanical activity raises oxygen demand during ischemia. Therefore, ideally, all electrical activity must cease during cardioplegia-induced cardiac arrest. Hypothermia, which in itself lowers basal metabolic rate and thus helps to reduce myocardial electrical activity, was used in thousands of operations in the early years of cardiac surgery. Topical cold saline or iced slush was poured over the heart into the pericardial cavity aft er aortic cross-clamping. Though effective for shorter periods of cross-clamping, this method becomes limiting following ischemic periods exceeding 1 hour. Subsequently, infusion of cold cardioplegia solutions into the myocardium to rapidly stop electromechanical activity and simultaneously reduce temperature in all myocardial layers has become the preferred method of cooling the heart.
Interventions that maximize high-energy phosphate production, while minimizing highenergy phosphate utilization and intracellular calcium accumulation during ischemia andreperfusion, are eff ective in delaying or preventing the onset of ischemic necrosis and inaiding recovery of function following reperfusion. Examples of methods to maximize highenergy phosphate production include preoperative glucose and glycogen loading, intraoperative
infusions of glucose, insulin and potassium, or the addition of Kreb’s cycle intermediates, glutamate and aspartate, to cardioplegic solutions.
The essential requirement for attainment of rapid diastolic cardiac arrest, however, renders potassium (20–40 mEq/l), which causes membrane depolarization, an essential ingredient of all cardioplegia solutions. Other components common to cardioplegia solutions include sodium (100–200 mEq/l)
and chloride ions. Sodium minimizes the transcellular sodium gradient and so reduces intracellular edema; marked extracellular hyponatremia (<50 mEql), together with excessive potassium-induced membrane depolarisation, alters the Na + /Ca 2+ exchange mechanisms in such a way as to promote intracellular Ca 2+ accumulation causing damage to sarcolemma membranes. Chloride ions maintain the electroneutrality of the solution. Modifi cation of cardioplegia to produce a solution that provides optimal preservation of myocardial function has led to a variety of additions to the “basic” ingredients, for example one of the most established blood cardioplegia preparations contains citrate phosphate dextrose (CPD), to limit calcium infl ux during ischemia, and tromethamine (tris-hydroxymethyl aminomethane, THAM), a buff er that prevents acidosis. THAM diff uses into the intravascular space, “captures” the CO 2 produced by metabolic acidosis and improves myocardial performance. Th e original cardioplegic solutions used for many years consisted of crystalloid solutions with various additives . Th e most widely used is the St. Th omas’ Hospital solution. Calcium , in low concentration, is included in the solution to ensure that there is no likelihood of calcium paradox during reperfusion and to maintain integrity of cell membranes. Magnesium may help stabilize the myocardial membrane by inhibiting a myosin phosphorylase, which protects ATP reserves for postischemic activity. Th e protective eff ects of magnesium and potassium have been shown to be additive. Procaine, a local anesthetic, is included in low concentration, to counteract the vasocontrictive eff ects of particulate contaminants in the infusion and so promote even distribution. St. Th omas’ solution is usually buff ered by the addition of sodium bicarbonate just prior to use; this renders the solution slightly alkaline and helps compensate for the metabolic acidosis that accompanies ischemia. Commercially prepared bags of ready diluted St. Th omas’ cardioplegia are available as an alternative to diluting the concentrate with Ringer’s, but diff er slightly from the original St Th omas’ preparation. Hypothermic crystalloid cardioplegia has certain disadvantages, including the fact that it inhibits the enzyme Na + /K + adenosine triphosphatase, which is intrinsic to the function of transmembrane ion pumps, thereby producing myocardial edema and consequent activation
of platelets, leukocytes and complement.
Cold Crystalloid Cardioplegia
There are basically two types of crystalloid cardioplegic solutions: the intracellular type and the extracellular type. The intracellular types are characterized by absent or low concentrations of sodium and calcium. The extracellular types contain relatively higher concentrations of sodium, calcium, and magnesium. Both types avoid concentrations of potassium 40 mmol/L, contain bicarbonate for buffering, and are osmotically balanced. In both types, the concentration of potassium used ranges between 10 and 40 mmol/L (for potassium 1 mmol/L 1 mEq/L).
Cold Blood Cardioplegia
Cold blood cardioplegia, widely employed throughout the world, is the cardioplegic technique used most commonly in the United States today. Although there are a variety of formulations, it is usually prepared by combining autologous blood obtained from the extracorporeal circuit while the patient is on cardiopulmonary bypass with a crystalloid solution consisting of citrate-phosphate-dextrose (CPD), tris-hydroxymethyl-aminomethane (tham) or bicarbonate (buffers), and potassium chloride. The CPD is used to lower the ionic calcium,the buffer is used to maintain an alkaline pH of approximately 7.8, and the final concentration of potassium is used to arrest the heart (approximately 30 mmol/L). Prior to administering blood cardioplegia, the temperatureof the solution usually is lowered with a heat-exchanging coil to between 12 and 4C. The ratio of blood to crystalloid varies among centers, with the most common ratios being8:1, 4:1, and 2:1. This, in turn, affects the final hematocrit of the blood cardioplegia infused. For example, if the hematocrit of the autologous blood obtained from the extracorporeal circuit is 30, these ratios would result in a blood cardioplegia with a hematocrit of approximately 27, 24, and 20, respectively. The use of undiluted blood cardioplegia, or “miniplegia” (using a minimum amount of crystalloid additives), also has been reported to be effective. In an acute ischemia-reperfusion canine preparation,Velez and colleagues tested the hypothesis that an all-blood cardioplegia (66:1 blood:crystalloid ratio) would provide superior protection compared with a 4:1 blood cardioplegia delivered in a continuous retrograde fashion. They found very little difference between the animal groups with respect to infarct size or postischemic recovery of function. This is consistent with the findings by Rousou and colleagues years earlier that it is the level of hypothermia that is important in blood cardioplegia, not necessarily the hematocrit.
Warm Blood Cardioplegia
The concept of using warm (normothermic) blood cardioplegia as a cardioprotective strategy in humans dates back to the 1980s. In 1982, Rosenkranz and colleagues reported that warm induction with normothermic blood cardioplegia,with a multidose cold blood cardioplegia maintenance of arrest, resulted in better recovery of function in canines than
a similar protocol using cold blood induction.88 In 1986, Teoh and colleagues reported an experimental study demonstrating that a terminal infusion of warm blood cardioplegia before removing the cross-clamp (a “hot shot”) accelerated myocardial metabolic recovery.89 This was followed by a report in 1991 by Lichtenstein and colleagues that normothermic blood cardioplegia in humans is an effective cardioprotective approach.90 They compared the results of 121 consecutive patients who received antegrade normothermic blood cardioplegia during MR operations with a historical group of 133 patients who received antegrade hypothermic blood cardioplegia. The operative mortality in the warm cardioplegic group was 0.9% compared with 2.2% for the historical controls. At about the same time, Salerno and colleagues reported a series of 113 consecutive patients in which/ continuous warm blood cardioplegia was administered via the coronary sinus.91 In this series, 96% had spontaneous return of rhythm on reperfusion, 7% needed transient IABP circulatory support, 6% had evidence of a perioperative MI, and 3% did not recover. A control cohort was not provided for comparison.
Despite these encouraging reports, there are still concerns with this approach. For example, for any given patient, it is not known just how long the warm heart can tolerate
an ischemic event, which may occur when the infusion is interrupted, flow rates are reduced owing to an obscured surgical field, or a maldistribution of the cardioplegic solution
occurs. Another concern is the report by Martin and colleagues that suggested that the use of warm cardioplegia is associated with increased incidence of neurologic deficits.92
In their prospective, randomized study (conducted on more than 1000 patients), the efficacies of warm blood cardioplegia and cold oxygenated crystalloid cardioplegia were analyzed. While operative mortalities were similar between the warm blood group and the cold oxygenated crystalloid cardioplegia cohort (1.0 versus 1.6%, respectively), the incidence of permanent neurologic deficits was threefold greater in the warm blood group (3.1 versus 1.0%). Thus, it appears that warm blood cardioplegia offers no distinct
advantage over cold blood or cold crystalloid cardioplegia, and it may be less than ideal if its delivery is interrupted for any reason.
Tepid Blood Cardioplegia
Both cold blood (4 to 10C) and warm blood cardioplegic solutions (37C) have temperature-related advantages anddisadvantages. As a consequence, a number of studies were
performed in the 1990s to determine the optimal temperature. Hayashida and colleagues were one of the first groups to study specifically the efficacy of tepid blood (29C) cardioplegia. 93 In this study, 72 patients undergoing CABG were randomized to receive cold (8C) antegrade or retrograde, tepid (29C) antegrade or retrograde, or warm (37C) antegrade or retrograde blood cardioplegia. While protection was adequate for all three, the tepid antegrade cardioplegia was the most effective in reducing anaerobic lactate acid release during the arrest period. These authors reported similar findings when the tepid solution was delivered continuously retrograde and intermittently antegrade.94 Since then, other studies also have demonstrated that tepid blood cardioplegia is safe and effective. The majority of these studies, however, have been single-center studies and/or conducted in a relatively small cohort of patients.Whether tepid cardioplegia confers better protection over other current methodologies remains to be determined
1. It can provide an oxygenated environment.
2. It can provide a method for intermittent reoxygenation
of the heart during arrest.
3. It can limit hemodilution when large volumes of
cardioplegia are used.
4. It has an excellent buffering capacity.
5. It has excellent osmotic properties.
6. The electrolyte composition and pH are physiologic.
7. It contains a number of endogenous antioxidants
and free-radical scavengers.
8. It can be less complex than other solutions to
prepare.
Blood cardioplegia largely replaced crystalloid cardioplegia in most centers several years ago. It consists of four parts of blood to one part crystalloid cardioplegia solution. Th is limits the systemic hemodilution seen with crystalloid cardioplegia during repeated infusions. Blood cardioplegia maintains oncotic pressure, is a natural buff ering agent, has advantageous rheological properties and is a free radical scavenger. It also limits reperfusion injury in the acutely ischemic myocardium. Experimental studies have shown that normal hearts subjected to up to 4 hours of ischemia have complete recovery of function when intermittent cold blood cardioplegia is infused. Cold blood cardioplegia alone, however, does not totally avoid njury. Th e Kreb’s cycle amino acids glutamate and aspartate are depleted during episodes of intermittent blood cardioplegia administration. Th ey are especially depleted in chronically ischemic hearts and may be replenished by using blood cardioplegia with added glutamate and aspartate, oft en referred to as “substrate-enhanced cardioplegia.” Blood cardioplegia, with or without substrate enhancement, may be infused as a warm solution to optimize the metabolic rate of repair, just prior to removal of the aortic cross-clamp, at the end of the intended ischemic period. Th is warm phase has been referred to as the “hot shot” of cardioplegia. It enhances cellular assimilation of the substrates (see Figure 7.2 ), augmenting the rate of recovery of myocardial contractility. Some surgeons also infuse a small volume of warm
blood cardioplegia followed by cold cardioplegia to induce cardiac arrest at the commencement of the ischemic period, on the basis that this “feeds” the heart, i.e., provides a more physiological delivery of oxygen and substrates for the period of ischemia.
Figure 7.2 (a) Left ventricular function in normal hearts subjected to 4 hours of aortic clamping with blood cardioplegia every 20 minutes compared with depressed function after 45 minutes of normothermic arrest without cardioplegia. (b) Left ventricular function when jeopardized hearts undergoing 45 minutes of normothermic ischemia are subjected to 2 more hours of aortic clamping. Note (1) no further improvement when only cold cardioplegic perfusate is given over the 45 minute arrest period, (2) progressively increased recovery when the cardioplegic solution is supplemented with warm glutamate and aspartate during induction of cardioplegia and reperfusion with intermittent cold doses of blood every 20 minutes of supplemental aortic clamping. LAP = left atrial pressure; SWI = stroke work index.
Periodic replenishment (1) maintains arrest, (2) restores desired levels of hypothermia, (3) buffers acidosis, (4) washes acid metabolites away which inhibit continued anaerobiosis, (5) replenisheshigh-energy phosphates if the cardioplegic solution is oxygenated, (6) restores substrates depleted during ischemia (7) counteracts edema with hyperosmolarity.
Surgeons have advocated the merits of various manifestations of cardioplegia. Th ere is ongoing controversy regarding the ideal composition, temperature (cold vs. warm), frequency of dosing and the route of administration (antegrade vs. retrograde) of cardioplegia. Th e “integrated method” of cardioplegia administration is a technique that combines the advantages of many strategies while addressing the immediate needs of the myocardium during a cardiac operation. It hastens the recovery of the myocardium while not interfering with visualization during the cardiac operation. Coronary artery bypass is the most common cardiac operation, and so is used here to illustrate this example of the integrated method. Cardiopulmonary bypass is fi rst initiated with cannulation of the aorta and right atrium and the core temperature is moderately reduced to about 34 ° C. Th e aorta is cross-clamped and the heart arrested with a cold cardioplegic mixture containing high-dose potassium (20 mEq/l) infused antegrade into the aortic root at a fl ow rate of 300 ml/minute for 2 minutes, followed by retrograde coronary sinus infusion at a fl ow rate of 200 ml/minute for 2 minutes. A diagram of a system used to deliver cold and warm cardioplegia via antegrade and retrograde routes and at low or high potassium strengths is shown in Figure 7.3 . Septal temperature is monitored with a temperature probe and usually falls to below 15°C. Topical hypothermia of the right ventricle may be supplemented with cold saline or iced saline slush with protection of the phrenic nerves to prevent postoperative palsy. Th is is not, however, mandatory. Th e right coronary is fi rst graft ed with saphenous vein. “Maintenance” low-dose cold potassium (8–10 mEq/l) blood cardioplegia is then infused simultaneously into the vein graft and coronary sinus at a fl ow rate of 200 ml/minute for 1 minute. Th e
vein graft is then sewn onto the aorta while a continuous non-cardioplegic solution of modified cold blood is infused at 200 ml/minute. Th is “modifi ed cold blood solution” (10°C) contains CPD, THAM, magnesium and mannitol and has been shown to provide better recovery than cold blood alone. Th e aorta is actively vented with suction applied to the cardioplegia catheter. Th e vent is discontinued and maintenance cardioplegia (low-dose cold potassium (8–10 mEq/l) blood cardioplegia) is infused into the aortic root at a fl ow of 200 ml/minute for 1 minute. Aft er residual air is displaced from the aorta and as the cardioplegia blood emerges, the surgeon completes the anastamosis of the proximal end of the vein graft . Th e above procedure is repeated until all vein graft anastomoses, except one, are complete. Aft er the last distal anastomosis is completed, the “hot shot” of warm substrate-enhanced cardioplegia is delivered, fi rst antegrade into the ascending aorta at 150 ml/minute for 2 minutes, then retrograde through the coronary sinus and simultaneously through the last unattached saphenous vein graft proximal end at 150 ml/minute for 2 minutes. Th ere is sometimes transient mild vasodilation due to the added amino acids and this is easily treated with neosynephrine (0.5 –1 μg/kg/minute). Th e fi nal distal anastomosis is that of the internal mammary to the left
anterior coronary artery. At this point the body and cardioplegia are re-warmed. As the last vein graft is sewn to the aorta, the cardioplegia is washed out of the myocardium by retrograde infusion of plain warm blood at a fl ow of 300 ml/minute. Th e heart begins contracting, slowly at fi rst, then more rapidly and vigorously. Th e cardioplegia delivery system is turned to the antegrade mode of delivery and warm blood is infused into the aortic root while the aorta is still clamped for another 3–5 minutes. During this time, the perfusionist adjusts the fl ow to maintain an aortic root pressure of about 80 mmHg. Air is purged from the coronary graft s with a fi ne needle. Th e aortic clamp is then removed and the patient weaned off bypass, usually within 5 minutes with minimal (dopamine 2.5 μg/kg/minute) or no inotropic support in spite of lengthy aortic clamp times. Defi brillation is very rarely needed. Note that the integrated method of protection involves a single period of aortic crossclamping, which serves to limit atheroembolic events. Ischemic times are actually shortened in spite of longer clamp times and morbidity and cost have been shown to be reduced with this technique.
Evolving myocardial infarction In patients with acute ischemia, or evolving myocardial infarction, the ventricle is ischemic and energy depleted because of lack of perfusion. The goal is to restore the depleted substrates and reverse ischemia by restoring flow with coronary graft s, while also preventing reperfusion injury to the myocardium. A substrate-enhanced low-potassium cardioplegia is used during these procedures, “acute MI/arrest” cardioplegia. Th is is a formulation that contains potassium to keep the heart arrested, a calcium channel blocker to prevent intracellular calcium infl ux and amino acid substrates to promote regeneration of high-energy phosphates. This solution is infused over a prolonged time (20 minutes). The normothermic arrested heart is replenished with the amino acid substrates aspartate and glutamate, which are rapidly assimilated into the myocardium to generate ATP needed for contractility. leukocyte depletion by adding filters to the cardioplegia in cases of acute infarction has also been shown to attenuate reperfusion injury.
Preservation of myocardial function during the ischemic period, that is, during the period in which the aorta is cross-clamped, is best achieved by putting the heart into a state of hibernation using a solution – generically termed “cardioplegia.” The purpose of cardioplegia is to cause rapid diastolic cardiac arrest. This produces a still, flaccid heart, which f facilitates surgery and also is the state in which myocardial metabolism is almost at its lowest levels. Further reduction in the metabolic state of the heart is achieved by cooling using cold cardioplegia and also by core cooling of the body.
Ischemic Preconditioning
Ischemic preconditioning is an adaptive biologic phenomenon in which the heart (and numerous other tissues) becomes more tolerant to a period of prolonged ischemia if
first exposed to a prior episode of brief ischemia and reperfusion. This adaptation to ischemia was first described by Murray and colleagues and is referred to as classic or earlyphase preconditioning.99 This increased tolerance to ischemia is associated with a reduction in infarct size, apoptosis, andreperfusion-associated arrhythmias.100–104 It has been demonstrated in every animal species studied and appears to persist as long as 1 to 2 hours after the ischemic preconditioning stimulus.105,106 It becomes ineffective when the sustained ischemic insult exceeds 3 hours.107 This suggests that he protection is conferred only when prolonged ischemia is followed by timely reperfusion.108
Subsequent studies have revealed that this endogenous defense mechanism can manifest itself in multiple ways. After the acute phase of preconditioning disappears, a second
phase of protection appears 24 hours later and is sustained for up to 72 hours. This has been referred to as the second window of protection, late-phase preconditioning, or
delayed preconditioning. Unlike classic preconditioning, which protects only against infarction, the late phase protects against both infarction and myocardial stunning.101,109 Concurrent with these reports is an additional observation that ischemia induced in other organs could precondition theheart, a phenomenon referred to as remote or interorgan preconditioning. 110 Remote myocardial preconditioning, whichhas been reported by multiple investigators in various species, can be induced by brief occlusions of the renal and
mesenteric arteries, as well as by skeletal muscle ischemia.111–114 More recent studies indicate that multiple, brief coronary occlusions during the initial minutes of reperfusion
following prolonged ischemia can reduce myocardial infarct size to a similar extent as ischemic preconditioning.115,116 This adaptive response is referred to as ischemic
postconditioning. These observations have resulted in major investigative efforts to elucidate the intracellular mechanism(s) that underlie the heart’s endogenous defenses against ischemiareperfusion injury. The assumption is that a better understanding of these mechanism(s) could lead to the development of potent new therapeutic modalities that are more effective in treating or preventing the deleterious consequences of ischemia-reperfusion injury. One of the earliest hypotheses was that stimulation of cardiomyocyte adenosine
A1 and/or A3 receptors was the primary mediator of acute ischemic preconditioning.106,117,118 Subsequent studies have shown, however, that in addition to adenosine, there re multiple guanine nucleotide-binding (G) protein–coupled receptors that, once activated, can mimic the infarct-reducing effect of ischemic preconditioning (e.g., bradykinin, endothelin, 1- adrenergic, muscarinic, angiotensin II, and delta-opioid receptors)103,119 (Fig. 15-4). Transient infusion of exogenous agents that mimic ischemic preconditioning is referred to as pharmacologic preconditioning. Exactly which of these receptors is the most important in mediating endogenous preconditioning is unknown because there appear to be species differences and redundant pathways. Regardless, it is now thought that these triggers of ischemic preconditioning result in alterations in certain enzymes, such as tyrosine kinases, protein kinase C (PKC) isoforms, and mitogen-activated protein kinases [p38 and extracellular signal regulated
kinase (ERK)] that, in turn, confer protection against irreversible injury prior to the onset of prolonged ischemia.103,117–119 While the actual effector(s) of the protection has(have) yet to be determined, significant evidence has accumulated indicating that the cardiomyocyte mitochondria appear both to play a primary role in triggering this protection and to be a key target of preconditioning-induced protection.103,117–121 While early-phase preconditioning shares many of the same signaling mechanisms with late-phase preconditioning, the most obvious difference between the two is the apparent requirement for protein synthesis in the latter. Both latephase ischemic and pharmacologic preconditioning have been shown to be associated with the upregulation of various proteins, including, but not limited to, heat-shock proteins, inducible NOS (iNOS), cyclooxygenase 2, and manganese superoxide dismutase.110,124 There are, however, conflicting reports on what specific proteins are upregulated during latephase
preconditioning, which may be due to species differences, as well as stimulus-specific responses.1
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MYOCARDIAL PRESERVATION
Since the publication of the first edition of this book, a wealth of literature has been generated concerning intraoperative protection of the paediatric
myocardium. A majority of the work reported in this literature is experimental and includes various modifications of crystalloid cardioplegic solutions, blood
cardioplegia and, more recently, reperfusion solutions.
Despite extensive literature, there remains no generally accepted strategy for the intraoperative protection of the paediatric myocardium. This is partly because the myocardium of neonates and infants is not the same as that of adult patients or animal models. The large number of different types of operations for congenital heart disease also makes comparison of different types of myocardial protection difficult. However, the principles of myocardial protection (i.e. diastolic arrest using high potassium concentrations, with ventricular decompression and hypothermia to reduce metabolic
demand) remain unchanged. There are major metabolic, functional and biochemical differences between the heart of a newborn and that of
an older child (Coles et al., 1987). The neonatal heart uses glucose as its principle energy source. Experimental evidence suggests that neonates are better able to tolerate hypoxia than are children, but are less tolerant of the increase in myocardial water associated with repeated doses of crystalloid cardioplegic solution (Grice et al., 1987; Yano et al., 1987). Thus, when using crystalloid cardioplegia, many surgeons use only a single dose for operations in newborns, extending up to about 80 minutes of aortic cross-clamping time. Others repeat cardioplegia every 20–30 minutes, as in older children.
The myocardium is also cooled topically with the use of repeated applications of ice slush during the period of cross-clamping, so as to reduce the temperature gradient between the heart and the surrounding tissues. Typically, following application of the aortic crossclamp, an initial dose of cardioplegia of 20–30ml/kg is given, and supplemental doses of 10 ml/kg are administered every 20–30 minutes. Cardioplegic solutions are usually delivered in a prograde manner into the aortic root, via a cardioplegic cannula placed through
a purse-string suture. In the presence of aortic (truncal valve) incompetence, the cardioplegic solution is infused through a coronary artery cannula directly into the coronary
arteries after opening of the aorta. Direct infusion into the coronary arteries is also used in all situations in which the aorta is opened (repair of truncus arteriosus, arterial switch operation). In experimental studies, various additives to the cardioplegic solution have been found to offer better protection of the myocardium. These include L-aspartate, L-glutamate, adenosine, calcium channel blockers, deferoxamine, co-enzyme Q10 and free radical scavengers. However, their precise role in clinical practice has not, as yet, been properly defined. It has been demonstrated experimentally (Rosenkranz et al., 1984) that the initial warm cardioplegic solution may optimize the conditions for myocardial recovery in the post-ischaemic period. Factors other than cardioplegia often contribute to the adequacy of myocardial preservation and must be borne in mind. These include
preoperative glycogen reserves, anaesthetic techniques,total body (perfusate) hypothermia, topical cooling, avoidance of coronary air embolization and avoidance of
distension of the heart. Gentle handling of the heart and the completeness of the surgical repair are also extremely important. Several experimental and some clinical studies have shown the superiority of providing oxygen in the cardioplegic solution. The vehicle for providing oxygen may be blood, perfluorocarbons, stroma-free haemoglobin,
or oxygen dissolved in crystalloid cardioplegic solution. Of these different agents, blood is the only vehicle that is used clinically. The advantages of blood in cardioplegia
include: (a) keeping the heart oxygenated while it is being arrested; (b) improved buffering and rheology; and (c) reducing the risk of reperfusion damage. Unlike in adult surgery, the advantages of blood cardioplegia in paediatric myocardial protection are less well established. There is evidence to support its useover crystalloid cardioplegia during periods of prolonged myocardial ischaemia (Corno et al., 1987). Induced ventricular fibrillation without aortic crossclamping is a useful technique for less complicated
lesions, in which the intracardiac procedure is short. It is usually combined with mild hypothermia and can be used in the majority of patients with secundum atrial septal
defects (Rosengart and Stark, 1993). This technique may also be used in operations involving the right ventricle, the right ventricular outflow tract, and the pulmonary
arteries. The technique is also useful whenever it is impossible to cross-clamp the aorta safely (e.g. in the presence of severe calcification). If induced fibrillation is
used, great care should be taken not to distend the heart because this would seriously impair myocardial blood flow and cause subendocardial ischaemia.
