- Email: [email protected]
Cardiac Recovery in a Human Non–Heart-beating Donor After Extracorporeal Perfusion: Source for Human Heart Donation?
CASE REPORTS
Cardiac Recovery in a Human Non–Heart-beating Donor After Extracorporeal Perfusion: Source for Human Heart Donation? Ayyaz Ali, MRCS,a Paul White, PhD,b Kumud Dhital, FRCS,a Marian Ryan, RGN,a Steven Tsui, FRCS,a and Stephen Large, FRCP, FRCSa Successful renal, liver and more recently lung transplantation using organs from non– heart-beating donors (NHBDs) has been reported. Regarding the heart, it has generally been assumed that warm ischemic insult would result in overwhelming and irreversible myocardial damage. We report recovery of cardiac function in a human NHBD by using extracorporeal perfusion 23 minutes after cardiorespiratory arrest. Successful cardiac resuscitation in the NHBD represents a potential source of increased donor organ supply for clinical heart transplantation. J Heart Lung Transplant 2009;28:290 –3. Copyright © 2009 by the International Society for Heart and Lung Transplantation.
Cardiac transplantation is the definitive treatment for end-stage heart failure. Unfortunately, a progressive decline in the number of suitable donor organs has limited activity worldwide.1 Over the past decade, there has been a progressive increase in the number of organs procured from non– heart-beating donors (NHBDs).2–5 In the UK, the number of transplants using organs from NHBDs increased by 44% in 2007.6 It is estimated that there are approximately 1,200 NHBDs annually in the UK. NHBDs undergo a cardiac arrest either in controlled or uncontrolled circumstances as categorized by the Maastrict classification.7 The duration of warm ischemia associated with cardiac arrest in an uncontrolled environment (Maastricht Categories I and II) limits the use of these organs. In the setting of controlled cardiac arrest, after withdrawal of supportive therapy (Maastricht Categories III and IV), access to the donor is allowed after a mandatory “stand-off” period during which death is confirmed. Renal, hepatic and more recently lung transplantation has been performed successfully using organs from NHBDs.8 –13 With regard to cardiac donation it has generally been considered that warm ischemia, with a possible contribution of anoxic neurologic injury, would lead to irreversible myocardial damage. We report successful resuscitation of a human NHBD
From the aDepartment of Cardiothoracic Surgery, Papworth Hospital, Papworth Everard, Cambridge; and bDepartment of Medical Physics and Clinical Engineering, Addenbrooke’s Hospital, Cambridge, UK. Submitted May 20, 2008; revised September 14, 2008; accepted December 1, 2008. Reprint requests: Ayyaz Ali, MD, Department of Cardiothoracic Surgery, Papworth Hospital, Papworth Everard, 10 Sandringham Drive, Cambridge CB3 8RE, UK. Telephone: 650-669-5776. Fax: 011-44-83-1540. E-mail: [email protected] Copyright © 2009 by the International Society for Heart and Lung Transplantation. 1053-2498/09/$–see front matter. doi:10.1016/ j.healun.2008.12.014
290
heart with functional recovery after rapid establishment of extracorporeal circulation in the donor. CASE REPORT A 57-year-old woman presented to the local hospital with sudden onset of headache. Her past medical history was limited to treated hypothyroidism. Her condition deteriorated and she developed right-sided hemiparesis and homononymous heminopia. A computerized tomography (CT) scan of her brain demonstrated a large intracranial bleed in the left parietal region, after which she was transferred to the regional neurosurgical unit. On arrival, she was unconscious with a Glasgow Coma Scale (GCS) score of 3. The patient was subsequently intubated and mechanically ventilated. She was hemodynamically stable without inotropic support and had normal renal and respiratory parameters. Her neurologic status was irrecoverable and, after discussion between her intensive-care physicians and immediate family, it was decided to withdraw therapy. She was a suitable candidate for non– heartbeating organ donation and informed consent was obtained by the local transplant coordinator for organ donation and research relating to cardiac resuscitation. The study was previously approved by our local research ethics committee. Mechanical ventilation was discontinued. The donor was extubated at 3:30 p.m. and became asystolic 1 minute later. A 5-minute stand-off period was observed to ensure the absence of any electrical cardiac activity, allowing confirmation of death. After this period elapsed, the donor was promptly transferred to the operating theater where the surgical teams were scrubbed and ready. The donor arrived into the operating theater at 3:47 p.m. and was transferred to the operating table. A median sternotomy incision was made at 3:50 p.m., the pericardium was opened, and the heart and great vessels exposed. On inspection, the heart was asystolic and moderately distended. A long
The Journal of Heart and Lung Transplantation Volume 28, Number 3
Ali et al.
cross-clamp was applied across the aortic arch vessels to prevent subsequent cerebral perfusion. Heparin 30,000 IU was injected into the right ventricle and massaged for adequate anti-coagulation prior to commencing perfusion. A therapeutic activated coagulation time of 407 seconds was measured 2 minutes later. In rapid succession, a 24Fr aortic cannula was introduced into the ascending aorta and then a 2-stage venous cannula into the right atrium for venous drainage. Normothermic cardiopulmonary bypass (CPB) was commenced 4 minutes after skin incision (3:54 p.m.), achieving extracorporeal flow of 4 liters/min (cardiac index 1.9 liter/min/m2). The interval between the last heart beat and re-establishment of the circulation was 23 minutes, this being the total warm ischemic period. Within 5 minutes of coronary reperfusion the heart initially fibrillated and spontaneously reverted into sinus rhythm at a rate of 90 beats/min. Arterial blood-gas analysis immediately after the onset of reperfusion revealed profound acidosis and mild hyperkalemia (Table 1). These metabolic abnormalities were corrected by a single administration of sodium bicarbonate and an insulin– dextrose infusion. Initially, the systemic vascular resistance (SVR) was low (500 dyne). After an infusion of vasopressin at a rate of 4 U/hour, a mean arterial pressure of 50 to 70 mm Hg was achieved and maintained throughout the period of extracorporeal perfusion. At this point, abdominal surgeons prepared the kidneys, both of which were successfully used for clinical transplantation. Right and left ventricular function of the human NHBD heart was measured using the pressure–volume conductance method.14 A conductance catheter was inserted into the right ventricle through the infundibulum. A second catheter was inserted into the ascending aorta and passed retrograde across the aortic valve into the left ventricle. The trachea was re-intubated, ventilation recommenced, and the patient weaned from CPB at 7:04 p.m. At this point, the heart was independently supporting the circulation. The mean arterial pressure was 55 mm Hg and the central venous pressure was 10 mm Hg. Pressure– volume loops were obtained from both the right and left ventricle at a constant heart rate (80 bpm) and body
291
temperature (36.5°C). Pressure–volume loops from the right and left ventricle of the NHBD are demonstrated in Figure 1b. Left ventricular systolic function compared favorably to normal (Figure 1b). An infusion of dopamine at 5.0 g/kg/min demonstrated contractile reserve in the left ventricle. However, the right ventricular loop morphology was abnormal with small stroke work. After dopamine infusion, the right ventricular pressure–volume loop assumed an abnormal configuration, which has previously been described after ischemia by Bishop et al. This morphology has been referred to as an “ischemic shoulder” and was noted to occur after occlusion of the right coronary artery.15 For comparison, right and left ventricular pressure–volume loops obtained from a normal heart and a brainstem-dead organ donor are depicted in Figure 1a and 1c, respectively. A Swan–Ganz catheter was introduced. Cardiac output was measured at 4.1 liters/min with a cardiac index of 2.4 liters/min/m2 and SVR of 878 dyne/s/cm5. The mean pulmonary artery pressure was 19 mm Hg and pulmonary capillary wedge pressure was 13 mm Hg, giving a pulmonary vascular resistance of 117 dyne/s/cm5. DISCUSSION We have described cardiac resuscitation in a humancontrolled NHBD after prompt establishment of extracorporeal perfusion. Despite a warm ischemic period of 23 minutes we demonstrated recovery of the heart. This is consistent with historical evidence suggesting that irreversible myocardial damage only occurs after 40 minutes in the normal empty, beating dog heart.16 Hearts from NHBDs are theoretically not exposed to injury associated with brainstem death.17 For this reason, we believe NHBD hearts will demonstrate improved function compared with those obtained from conventional brainstem-dead donors. The continual decrease in the number of brainstem-dead donors has been accompanied by a progressive increase in non– heart-beating organ donation.5,6 To assess recovery of cardiac contractile function in the resuscitated NHBD heart we employed the pressure–volume conductance
Table 1. Hemodynamic and Biochemical Data During Extracorporeal Perfusion Time 3:54 4:45 5:15 5:45 6:15 6:45 7:00
p.m. p.m. p.m. p.m. p.m. p.m. p.m.
Flow (liters/min)
Mean arterial pressure (mm Hg)
H⫹ (mmol/liter)
PCO2 (mm Hg)
PO2 (mm Hg)
Hb (g/dl)
SVO2 (%)
K⫹ (mmol/liter)
4.0 5.8 6.0 5.8 4.6 5.3 4.8
40 53 65 68 63 69 69
81.4 41.6 35.4 35.8 33.4 34.2 44.5
61 37 34 39 38 37 48.1
232 195 273 241 263 210 163
6.4 6.5 6.7 6.9 5.6 5.9 7.7
64 53 61 58 55 57 56
6.1 4.6 4.5 4.7 4.5 4.5 4.8
ACT (s) 407 442 430 407
Body type indicates marked derangement of this value compared to normal, highlighting the metabolic derangement that was present at the start of perfusion.
292
Ali et al.
The Journal of Heart and Lung Transplantation March 2009
Figure 1. Pressure–volume loops from right and left ventricles. (a) Normal human heart. Left and right ventricular pressure–volume loops from normal human heart. (b) Resuscitated non– heart-beating donor heart. Pressure–volume loops from the right and left ventricle of a non– heart-beating donor. The left ventricle demonstrated contractile reserve after infusion of dopamine as indicated by an upward and leftward shift of the end-systolic pressure–volume relationship (ESPVR) The right ventricular pressure–volume loop appears abnormal due to a decreased stroke work (pre-dopamine). Ischemia of the right ventricle resulted in an “ischemic shoulder,” a previously described alteration in pressure–volume loop morphology of the right ventricle in response to ischemia. (c) Brainstem-dead donor heart. Left and right ventricular pressure–volume loops from a heart-beating brainstem-dead donor. Both ventricles demonstrated no contractile reserve after infusion of dopamine, indicated by a reduction in the end-systolic pressure–volume relationship (downward and rightward shift of the ESPVR).
The Journal of Heart and Lung Transplantation Volume 28, Number 3
method, a reproducible load-independent means of assessing cardiac function, as described elsewhere.14. The right ventricular pressure–volume loop is normally triangular in shape and, in response to ischemia, it assumes a rectangular shape analogous to that of the left ventricle.15 Despite the apparent impairment of right ventricular contractility indicated by our data, the central venous pressure did not exceed 12 mm Hg and the mean pulmonary artery pressure was 19 mm Hg with a PVR of 117 dyne/s/cm,5 confirming adequate right ventricular function. The heart was able to independently support the circulation for 37 minutes with a good cardiac index confirming effective functional recovery. To date, hearts from NHBDs have not been transplanted at our institution, as ethical approval for a clinical program is pending. Cardiac transplantation as a treatment for severe heart failure is under threat due to a severe shortage of donor organs. This report of recovery in the human NHBD heart represents an exciting potential development in clinical heart transplantation. This source may allow for a significant increase in the number of donor hearts. A review of the Gift of Life Donor Program in Pennsylvania has documented that use of NHBDs can potentially expand the donor pool. Further assessment of hearts from human NHBDs is essential to confirm their viability. Although our report has described in vivo cardiac resuscitation the use of ex vivo machine perfusion may be a logical means for avoiding ethical issues associated with cardiac re-animation in donors who have been declared dead on the basis of loss of cardiac function. Ex vivo perfusion of donor hearts aims to replace conventional preservation strategies involving cold storage with blood perfusion, thereby minimizing the potential for ischemic injury. Collins et al investigated the use of machine perfusion for donor heart preservation and, in particular, commented on the suitability of such methods for supporting cardiac donation from NHBDs.18 Continued investigation in both human NHBD and animal models is necessary to improve our understanding of the heart after resuscitation following such profound global myocardial ischemia. Our work suggests that hearts from controlled NHBDs may be suitable for use in clinical cardiac transplantation and serves to remind us that the world’s first heart transplant, undertaken by Dr Christian Barnard in 1967, used a heart from a non– heart-beating donor.
Ali et al.
293
REFERENCES 1. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twentythird official adult heart transplantation report—2006. J Heart Lung Transplant 2006;25:869 –79. 2. Nunez JR, Del Rio F, Lopez E, et al. Non– heart-beating donors: an excellent choice to increase the donor pool. Transplant Proc 2005;37:3651– 4. 3. Del Rio Gallegos F, Nunez Pena JR, Soria Garcia A, et al. Non heart beating donors. Successfully expanding the donor’s pool. Ann Transplant 2004;9:19 –20. 4. Reiner M, Cornell D, Howard RJ. Development of a successful non-heart beating organ donation program. Progr Transplant 2003;13:225–31. 5. Campbell GM, Sutherland FR. Non-heart-beating organ donors as a source of kidneys for transplantation: a chart review. Can Med Assoc J 1999;160:1573– 6. 6. Yearly Statistics—Non-heart beating donors. www.uktransplant. org.uk/statistics/yearly_statistics. 7. Booster MH, Wijnen RM, Ming Y, et al. In situ perfusion of kidneys from non-heart-beating donors: the Maastricht protocol. Transplant Proc 1993;25:1503– 4. 8. Koffman G, Gambaro G. Renal transplantation from non-heart beating donors: a review of the European experience. J Nephrol 2003;16:334 – 41. 9. Abt P, Crawford M, Desai N, et al. Liver transplantation from controlled non-heart-beating donors: an increased incidence biliary complications. Transplantation 2003;75:1659 – 63. 10. Fukimori T, Kato T, Levi D, et al. Use of older controlled non-heart-beating donors for liver transplantation. Transplantation 2003;75:1171– 4. 11. Sudhindran S, Pettigrew GJ, Drain A, et al. Outcome of transplantation using kidneys from controlled (Maastricht category 3) nonheart-beating donors. Clin Transplant 2003;17:93–100. 12. Steen S, Sjoberg T, Pierre L, et al. Transplantation of lungs from a non-heart-beating donor. Lancet 2001;357:825–9. 13. Sanchez-Fructuoso AI, de Miguel Marques M, Prats D, et al. Non-heart-beating donors: experience from the hospital clinico of Madrid. J Nephrol 2003;16:387–92. 14. Connelly KA, Prior DL, Kelly DJ, et al. Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures. Am J Physiol Heart Circ Physiol 2006;290:H1699 –705. 15. Bishop A, White P, Groves P, et al. Right ventricular dysfunction during coronary artery occlusion: pressure–volume analysis using conductance catheters during coronary angioplasty. Heart 1997;78: 480 –7. 16. Danforth WH, Neagle S, Bing RJ. Effect of ischemia and reoxygenation on glycolytic reactions and adenosine triphosphate in heart muscle. Circ Res 1960;8:965. 17. Novitzky D, Wicomb DM, Cooper DKC, et al. Electrocardiographic, hemodynamic, and endocrine changes occuring during experimental brain death in the Chacma baboon. Heart Transplant 1984;4:63–9. 18. Collins MJ, Moainie SL, Griffith PB, et al. Preserving and evaluating hearts with ex vivo machine perfusion: an avenue to perform early graft performance and expand the donor pool. Eur J Cardiothorac Surg 2008;34:318 –25.
Cardiac Recovery in a Human Non–Heart-beating Donor After Extracorporeal Perfusion: Source for Human Heart Donation? Ayyaz Ali, MRCS,a Paul White, PhD,b Kumud Dhital, FRCS,a Marian Ryan, RGN,a Steven Tsui, FRCS,a and Stephen Large, FRCP, FRCSa Successful renal, liver and more recently lung transplantation using organs from non– heart-beating donors (NHBDs) has been reported. Regarding the heart, it has generally been assumed that warm ischemic insult would result in overwhelming and irreversible myocardial damage. We report recovery of cardiac function in a human NHBD by using extracorporeal perfusion 23 minutes after cardiorespiratory arrest. Successful cardiac resuscitation in the NHBD represents a potential source of increased donor organ supply for clinical heart transplantation. J Heart Lung Transplant 2009;28:290 –3. Copyright © 2009 by the International Society for Heart and Lung Transplantation.
Cardiac transplantation is the definitive treatment for end-stage heart failure. Unfortunately, a progressive decline in the number of suitable donor organs has limited activity worldwide.1 Over the past decade, there has been a progressive increase in the number of organs procured from non– heart-beating donors (NHBDs).2–5 In the UK, the number of transplants using organs from NHBDs increased by 44% in 2007.6 It is estimated that there are approximately 1,200 NHBDs annually in the UK. NHBDs undergo a cardiac arrest either in controlled or uncontrolled circumstances as categorized by the Maastrict classification.7 The duration of warm ischemia associated with cardiac arrest in an uncontrolled environment (Maastricht Categories I and II) limits the use of these organs. In the setting of controlled cardiac arrest, after withdrawal of supportive therapy (Maastricht Categories III and IV), access to the donor is allowed after a mandatory “stand-off” period during which death is confirmed. Renal, hepatic and more recently lung transplantation has been performed successfully using organs from NHBDs.8 –13 With regard to cardiac donation it has generally been considered that warm ischemia, with a possible contribution of anoxic neurologic injury, would lead to irreversible myocardial damage. We report successful resuscitation of a human NHBD
From the aDepartment of Cardiothoracic Surgery, Papworth Hospital, Papworth Everard, Cambridge; and bDepartment of Medical Physics and Clinical Engineering, Addenbrooke’s Hospital, Cambridge, UK. Submitted May 20, 2008; revised September 14, 2008; accepted December 1, 2008. Reprint requests: Ayyaz Ali, MD, Department of Cardiothoracic Surgery, Papworth Hospital, Papworth Everard, 10 Sandringham Drive, Cambridge CB3 8RE, UK. Telephone: 650-669-5776. Fax: 011-44-83-1540. E-mail: [email protected] Copyright © 2009 by the International Society for Heart and Lung Transplantation. 1053-2498/09/$–see front matter. doi:10.1016/ j.healun.2008.12.014
290
heart with functional recovery after rapid establishment of extracorporeal circulation in the donor. CASE REPORT A 57-year-old woman presented to the local hospital with sudden onset of headache. Her past medical history was limited to treated hypothyroidism. Her condition deteriorated and she developed right-sided hemiparesis and homononymous heminopia. A computerized tomography (CT) scan of her brain demonstrated a large intracranial bleed in the left parietal region, after which she was transferred to the regional neurosurgical unit. On arrival, she was unconscious with a Glasgow Coma Scale (GCS) score of 3. The patient was subsequently intubated and mechanically ventilated. She was hemodynamically stable without inotropic support and had normal renal and respiratory parameters. Her neurologic status was irrecoverable and, after discussion between her intensive-care physicians and immediate family, it was decided to withdraw therapy. She was a suitable candidate for non– heartbeating organ donation and informed consent was obtained by the local transplant coordinator for organ donation and research relating to cardiac resuscitation. The study was previously approved by our local research ethics committee. Mechanical ventilation was discontinued. The donor was extubated at 3:30 p.m. and became asystolic 1 minute later. A 5-minute stand-off period was observed to ensure the absence of any electrical cardiac activity, allowing confirmation of death. After this period elapsed, the donor was promptly transferred to the operating theater where the surgical teams were scrubbed and ready. The donor arrived into the operating theater at 3:47 p.m. and was transferred to the operating table. A median sternotomy incision was made at 3:50 p.m., the pericardium was opened, and the heart and great vessels exposed. On inspection, the heart was asystolic and moderately distended. A long
The Journal of Heart and Lung Transplantation Volume 28, Number 3
Ali et al.
cross-clamp was applied across the aortic arch vessels to prevent subsequent cerebral perfusion. Heparin 30,000 IU was injected into the right ventricle and massaged for adequate anti-coagulation prior to commencing perfusion. A therapeutic activated coagulation time of 407 seconds was measured 2 minutes later. In rapid succession, a 24Fr aortic cannula was introduced into the ascending aorta and then a 2-stage venous cannula into the right atrium for venous drainage. Normothermic cardiopulmonary bypass (CPB) was commenced 4 minutes after skin incision (3:54 p.m.), achieving extracorporeal flow of 4 liters/min (cardiac index 1.9 liter/min/m2). The interval between the last heart beat and re-establishment of the circulation was 23 minutes, this being the total warm ischemic period. Within 5 minutes of coronary reperfusion the heart initially fibrillated and spontaneously reverted into sinus rhythm at a rate of 90 beats/min. Arterial blood-gas analysis immediately after the onset of reperfusion revealed profound acidosis and mild hyperkalemia (Table 1). These metabolic abnormalities were corrected by a single administration of sodium bicarbonate and an insulin– dextrose infusion. Initially, the systemic vascular resistance (SVR) was low (500 dyne). After an infusion of vasopressin at a rate of 4 U/hour, a mean arterial pressure of 50 to 70 mm Hg was achieved and maintained throughout the period of extracorporeal perfusion. At this point, abdominal surgeons prepared the kidneys, both of which were successfully used for clinical transplantation. Right and left ventricular function of the human NHBD heart was measured using the pressure–volume conductance method.14 A conductance catheter was inserted into the right ventricle through the infundibulum. A second catheter was inserted into the ascending aorta and passed retrograde across the aortic valve into the left ventricle. The trachea was re-intubated, ventilation recommenced, and the patient weaned from CPB at 7:04 p.m. At this point, the heart was independently supporting the circulation. The mean arterial pressure was 55 mm Hg and the central venous pressure was 10 mm Hg. Pressure– volume loops were obtained from both the right and left ventricle at a constant heart rate (80 bpm) and body
291
temperature (36.5°C). Pressure–volume loops from the right and left ventricle of the NHBD are demonstrated in Figure 1b. Left ventricular systolic function compared favorably to normal (Figure 1b). An infusion of dopamine at 5.0 g/kg/min demonstrated contractile reserve in the left ventricle. However, the right ventricular loop morphology was abnormal with small stroke work. After dopamine infusion, the right ventricular pressure–volume loop assumed an abnormal configuration, which has previously been described after ischemia by Bishop et al. This morphology has been referred to as an “ischemic shoulder” and was noted to occur after occlusion of the right coronary artery.15 For comparison, right and left ventricular pressure–volume loops obtained from a normal heart and a brainstem-dead organ donor are depicted in Figure 1a and 1c, respectively. A Swan–Ganz catheter was introduced. Cardiac output was measured at 4.1 liters/min with a cardiac index of 2.4 liters/min/m2 and SVR of 878 dyne/s/cm5. The mean pulmonary artery pressure was 19 mm Hg and pulmonary capillary wedge pressure was 13 mm Hg, giving a pulmonary vascular resistance of 117 dyne/s/cm5. DISCUSSION We have described cardiac resuscitation in a humancontrolled NHBD after prompt establishment of extracorporeal perfusion. Despite a warm ischemic period of 23 minutes we demonstrated recovery of the heart. This is consistent with historical evidence suggesting that irreversible myocardial damage only occurs after 40 minutes in the normal empty, beating dog heart.16 Hearts from NHBDs are theoretically not exposed to injury associated with brainstem death.17 For this reason, we believe NHBD hearts will demonstrate improved function compared with those obtained from conventional brainstem-dead donors. The continual decrease in the number of brainstem-dead donors has been accompanied by a progressive increase in non– heart-beating organ donation.5,6 To assess recovery of cardiac contractile function in the resuscitated NHBD heart we employed the pressure–volume conductance
Table 1. Hemodynamic and Biochemical Data During Extracorporeal Perfusion Time 3:54 4:45 5:15 5:45 6:15 6:45 7:00
p.m. p.m. p.m. p.m. p.m. p.m. p.m.
Flow (liters/min)
Mean arterial pressure (mm Hg)
H⫹ (mmol/liter)
PCO2 (mm Hg)
PO2 (mm Hg)
Hb (g/dl)
SVO2 (%)
K⫹ (mmol/liter)
4.0 5.8 6.0 5.8 4.6 5.3 4.8
40 53 65 68 63 69 69
81.4 41.6 35.4 35.8 33.4 34.2 44.5
61 37 34 39 38 37 48.1
232 195 273 241 263 210 163
6.4 6.5 6.7 6.9 5.6 5.9 7.7
64 53 61 58 55 57 56
6.1 4.6 4.5 4.7 4.5 4.5 4.8
ACT (s) 407 442 430 407
Body type indicates marked derangement of this value compared to normal, highlighting the metabolic derangement that was present at the start of perfusion.
292
Ali et al.
The Journal of Heart and Lung Transplantation March 2009
Figure 1. Pressure–volume loops from right and left ventricles. (a) Normal human heart. Left and right ventricular pressure–volume loops from normal human heart. (b) Resuscitated non– heart-beating donor heart. Pressure–volume loops from the right and left ventricle of a non– heart-beating donor. The left ventricle demonstrated contractile reserve after infusion of dopamine as indicated by an upward and leftward shift of the end-systolic pressure–volume relationship (ESPVR) The right ventricular pressure–volume loop appears abnormal due to a decreased stroke work (pre-dopamine). Ischemia of the right ventricle resulted in an “ischemic shoulder,” a previously described alteration in pressure–volume loop morphology of the right ventricle in response to ischemia. (c) Brainstem-dead donor heart. Left and right ventricular pressure–volume loops from a heart-beating brainstem-dead donor. Both ventricles demonstrated no contractile reserve after infusion of dopamine, indicated by a reduction in the end-systolic pressure–volume relationship (downward and rightward shift of the ESPVR).
The Journal of Heart and Lung Transplantation Volume 28, Number 3
method, a reproducible load-independent means of assessing cardiac function, as described elsewhere.14. The right ventricular pressure–volume loop is normally triangular in shape and, in response to ischemia, it assumes a rectangular shape analogous to that of the left ventricle.15 Despite the apparent impairment of right ventricular contractility indicated by our data, the central venous pressure did not exceed 12 mm Hg and the mean pulmonary artery pressure was 19 mm Hg with a PVR of 117 dyne/s/cm,5 confirming adequate right ventricular function. The heart was able to independently support the circulation for 37 minutes with a good cardiac index confirming effective functional recovery. To date, hearts from NHBDs have not been transplanted at our institution, as ethical approval for a clinical program is pending. Cardiac transplantation as a treatment for severe heart failure is under threat due to a severe shortage of donor organs. This report of recovery in the human NHBD heart represents an exciting potential development in clinical heart transplantation. This source may allow for a significant increase in the number of donor hearts. A review of the Gift of Life Donor Program in Pennsylvania has documented that use of NHBDs can potentially expand the donor pool. Further assessment of hearts from human NHBDs is essential to confirm their viability. Although our report has described in vivo cardiac resuscitation the use of ex vivo machine perfusion may be a logical means for avoiding ethical issues associated with cardiac re-animation in donors who have been declared dead on the basis of loss of cardiac function. Ex vivo perfusion of donor hearts aims to replace conventional preservation strategies involving cold storage with blood perfusion, thereby minimizing the potential for ischemic injury. Collins et al investigated the use of machine perfusion for donor heart preservation and, in particular, commented on the suitability of such methods for supporting cardiac donation from NHBDs.18 Continued investigation in both human NHBD and animal models is necessary to improve our understanding of the heart after resuscitation following such profound global myocardial ischemia. Our work suggests that hearts from controlled NHBDs may be suitable for use in clinical cardiac transplantation and serves to remind us that the world’s first heart transplant, undertaken by Dr Christian Barnard in 1967, used a heart from a non– heart-beating donor.
Ali et al.
293
REFERENCES 1. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twentythird official adult heart transplantation report—2006. J Heart Lung Transplant 2006;25:869 –79. 2. Nunez JR, Del Rio F, Lopez E, et al. Non– heart-beating donors: an excellent choice to increase the donor pool. Transplant Proc 2005;37:3651– 4. 3. Del Rio Gallegos F, Nunez Pena JR, Soria Garcia A, et al. Non heart beating donors. Successfully expanding the donor’s pool. Ann Transplant 2004;9:19 –20. 4. Reiner M, Cornell D, Howard RJ. Development of a successful non-heart beating organ donation program. Progr Transplant 2003;13:225–31. 5. Campbell GM, Sutherland FR. Non-heart-beating organ donors as a source of kidneys for transplantation: a chart review. Can Med Assoc J 1999;160:1573– 6. 6. Yearly Statistics—Non-heart beating donors. www.uktransplant. org.uk/statistics/yearly_statistics. 7. Booster MH, Wijnen RM, Ming Y, et al. In situ perfusion of kidneys from non-heart-beating donors: the Maastricht protocol. Transplant Proc 1993;25:1503– 4. 8. Koffman G, Gambaro G. Renal transplantation from non-heart beating donors: a review of the European experience. J Nephrol 2003;16:334 – 41. 9. Abt P, Crawford M, Desai N, et al. Liver transplantation from controlled non-heart-beating donors: an increased incidence biliary complications. Transplantation 2003;75:1659 – 63. 10. Fukimori T, Kato T, Levi D, et al. Use of older controlled non-heart-beating donors for liver transplantation. Transplantation 2003;75:1171– 4. 11. Sudhindran S, Pettigrew GJ, Drain A, et al. Outcome of transplantation using kidneys from controlled (Maastricht category 3) nonheart-beating donors. Clin Transplant 2003;17:93–100. 12. Steen S, Sjoberg T, Pierre L, et al. Transplantation of lungs from a non-heart-beating donor. Lancet 2001;357:825–9. 13. Sanchez-Fructuoso AI, de Miguel Marques M, Prats D, et al. Non-heart-beating donors: experience from the hospital clinico of Madrid. J Nephrol 2003;16:387–92. 14. Connelly KA, Prior DL, Kelly DJ, et al. Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures. Am J Physiol Heart Circ Physiol 2006;290:H1699 –705. 15. Bishop A, White P, Groves P, et al. Right ventricular dysfunction during coronary artery occlusion: pressure–volume analysis using conductance catheters during coronary angioplasty. Heart 1997;78: 480 –7. 16. Danforth WH, Neagle S, Bing RJ. Effect of ischemia and reoxygenation on glycolytic reactions and adenosine triphosphate in heart muscle. Circ Res 1960;8:965. 17. Novitzky D, Wicomb DM, Cooper DKC, et al. Electrocardiographic, hemodynamic, and endocrine changes occuring during experimental brain death in the Chacma baboon. Heart Transplant 1984;4:63–9. 18. Collins MJ, Moainie SL, Griffith PB, et al. Preserving and evaluating hearts with ex vivo machine perfusion: an avenue to perform early graft performance and expand the donor pool. Eur J Cardiothorac Surg 2008;34:318 –25.