Intensive Care Med (1992) 18:493-495

IntensiveCare Medicine 9 Springer-Verlag 1992

Hemodynamic responses to noxious stimuli in brain-dead organ donors H.-J. G r a m m 1, J. Z i m m e r m a n n 1, H . M e i n h o l d 2, R. D e n n h a r d t 3 a n d K. Voigt 4 Department of 2Department of 3Department of 4Department of

Anesthesiology and Critical Care Medicine, Steglitz Medical Center, Free University of Berlin, Berlin, FRG Nuclear Medicine, Steglitz Medical Center, Free University of Berlin, Berlin, FRG Anesthesiology, Nordwest Hospital, Frankfurt/Main, FRG Physiology, Philipps University, Marburg, FRG

Received: 26 August 1991; accepted: 30 June 1992

Abstract. T h e case r e p o r t presents evidence for the spinal origin o f t h e m a r k e d hypertensive reponses to n o x i o u s stimuli t h a t m a y occur in o r g a n d o n o r s w h o fulfill the c o m m o n l y a c c e p t e d criteria o f b r a i n death. C a r d i o v a s c u lar spinal reflex activity does n o t invalidate these criteria. F o r t h e first time, the c a t e c h o l a m i n e p l a s m a c o n c e n t r a tions have b e e n d e t e r m i n e d d u r i n g spinal pressor reflex activity. C i r c u l a t i n g e p i n e p h r i n e increased m o r e m a r k e d ly t h a n n o r e p i n e p h r i n e in b o t h cases, rising to 4.7 a n d 44 times t h e baseline c o n c e n t r a t i o n respectively. T h e relation b e t w e e n p l a s m a n o r p i n e p h r i n e a n d e p i n e p h r i n e suggests involvement o f t h e a d r e n a l m e d u l l a in the reflex arc. T h e literature o n spinal h e m o d y n a m i c reflexes is reviewed. Key words: Brain d e a t h matisms - Organ donor

S p i n a l reflexes a n d a u t o -

B r a i n d e a t h is d e f i n e d as the irreversible loss o f cerebral a n d b r a i n - s t e m function, i n c l u d i n g t h a t o f the m e d u l l a o b l o n g a t a . T h e m a i n t e n a n c e o r r e a p p e a r a n c e o f spinal f u n c t i o n does n o t rule o u t b r a i n death. T h e reflex behavi o r o f b r a i n - d e a d p o t e n t i a l o r g a n d o n o r s in response to m e c h a n i c a l a n d n o x i o u s stimuli has b e e n e x a m i n e d in a n u m b e r o f studies, a n d spinal m o t o r reflexes have b e e n d e s c r i b e d in detail [1, 2]. Even c o m p l e x m o v e m e n t sequences have been o b s e r v e d as spinal a u t o m a t i s m s [3]. O n t h e o t h e r h a n d , o n l y little has b e e n r e p o r t e d so far o n h e m o d y n a m i c responses to n o x i o u s stimuli in b r a i n - d e a d o r g a n d o n o r s [ 4 - 6]. T h e o c c u r r e n c e o f this p h e n o m e n o n r e g u l a r l y leads to c o n f u s i o n in m e d i c a l p e r s o n n e l dealing w i t h o r g a n d o n a t i o n , w h o s o m e t i m e s go as far as to doubt the actual brain death. W i t h i n t h e context o f a s t u d y o n t h e e n d o c r i n e systems in 30 consecutive b r a i n - d e a d o r g a n d o n o r s , t h e dev e l o p m e n t o f a p r o n o u n c e d arterial h y p e r t e n s i o n was o b served in 2 d o n o r s after skin incision for o r g a n retrieval. P l a s m a c a t e c h o l a m i n e c o n c e n t r a t i o n s d u r i n g this res p o n s e were d e t e r m i n e d for t h e first time. T h e case r e p o r t thus allows c o n c l u s i o n s w i t h regard to the p a t h o -

m e c h a n i s m o f spinal h e m o d y n a m i c reflex activity in b r a i n death.

Case reports Case 1 A 47-year-old man developed an intractable increase in intracranial pressure after isolated craniocerebral trauma with bleeding in the ventricular system and fulfilled the criteria for brain death 7 days after the accident. Brain death was established according to the recommendations laid down by the German Medical Council [7]. Cerebral panangiography showed a complete intracranial circulatory arrest. The patient had had no illnesses or previous operations. His family gave their consent to multiorgan donation, which was performed 21 h after the onset of brain death. Body temperature was 33.9 ~ To control diabetes insipidus, the patient had reveived a single dose of 2 ~g DDAVP (Minirin | intravenously before the onset of brain death. The hematocrit was 34.8%. The plasma concentrations of hemodynamicaily relevant hormones were as follows: free thyroxine (FT4) 12.4 pmol/1, flee triiodothyronine (FT3) 2.3 pmol/1, adrenocorticotropic hormone (ACTH) 14.8 pg/ml and cortisol 3.2 gg/dl. The patient needed no pressor support. Heart rate and arterial blood pressure were monitored continuously during intensive care and harvesting. Seven blood samples were obtained after brain death, 2 of them during organ harvest. The blood specimens were immediately placed in pre-chilled EDTA tubes. Plasma was separated in a refrigerated centrifuge at 4 ~ and stored at -70 ~ until analysis. Plasma norepinephrine, epinephrine and dopamine concentrations were determined by high-performance liquid chromatography with electrochemical detection as described previously [8]. The hemodynamic variables before transfer to the operating theater were as follows: arterial pressure 102+_2/59+_2mmHg, heart rate 80+_0/min, cardiac output 5.0 +__0.21/min, pulmonary artery pressure 31/23 mmHg, pulmonary capillary wedge pressure 16 mmHg and central venous pressure 12 mmHg. Baseline levels were 307_+40 pg/ml for norepinephrine, 19+ 13 pg/ml for epinephrine and 32+_12 pg/ml for dopamine. Plasma cateeholamines showed the characteristic picture of decreased circulating epinephrine after brain death. Immediately after skin incision, arterial blood pressure rose to 220/115 mmHg. It reached a peak of 230/118 mmHg 3 min thereafter and then declined again. The mean arterial pressure rose by 110%. Parallel to the rise in blood pressure, heart rate increased from 80-108/min and had declined again to 81/min by the end of the organ donation (Fig. 1a). During arterial hypertension, plasma norepinephrine rose to 1340 pg/ml and epinephrine to 850 pg/ml, i.e. 4.4 and 44 times the base-

494 line values respectively. Circulating dopamine rose to 76 pg/ml, more than twice the baseline value. The ratio between plasma epinephrine and norepinephrine was 1 : 1.6 during versus 1 : 16 before hypertension (Fig. 1 b). A second moderate blood-pressure increase to 160/83 mmHg was observed after the aortic crossclamping.

a 4.7-fold increase in the plasma epinephrine concentration to 370 pg/ml and a 2.l-fold increase in the dopamine concentration to 54 pg/ml. The increase in circulating catecholamines was altogether less pronounced than in case 1.

Discussion Case 2 A 61-year-old female patient died 11 days after subarachnoid hemorrhage. A secondary diagnosis was hypertension. After angiographic confirmation of brain death and consent of the family to organ donation, a renal harvest was carried out 14 h after brain death. Body temperature was 35.5 ~ The patient did not develop any episode of diabetes insipidus. Plasma cortisol was 17.3~tg/dl and serum FT 3 1.6 pmol/1. Persistent hypotension a few hours after the onset of brain death required hemodynamic stabilization with dobutamine at a dosage of 14.3 gg/kg/min and norepinephrine at a dosage of 0.12 gg/kg/min. Immediately prior to organ harvest, arterial blood pressure was 96/53 mmHg, heart rate 102/rain, pulmonary capillary wedge pressure and central venous pressure 13 and 12 mmHg respectively and cardiac output 8.91/min. Circulating catecholamine levels were determined as follows: norepinephrine 1700 pg/ml, epinephrine 79 pg/ml and dopamine 26 pg/ml. Immediately after the initiation of surgery, the blood pressure rose to 127/72 mmHg, which corresponds to a 30% increase in mean arterial pressure. On the other hand, the heart rate only increased to 105/rain. The plasma norepinephrine level rose by 41% to 2400 pg/ml. There was

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These case reports demonstrate the possibility of marked hemodynamic responses to operative stimuli in potential organ donors who fulfill the commonly accepted criteria of brain death. Pressor responses to noxious stimuli that do not involve the brain stem have been demonstrated in decapitated animals [9]. In spinal animals, surgical procedures in the abdominal cavity can produce contractions of the leg and abdominal muscles and can raise the blood pressure as well as the heart rate. In man, spinal cardiovascular reflexes were noted by Conci et al. in 24o70 of organ donors during harvest operations, but only when the parietal peritoneum and splanchnic nerves were directly stimulated [6]. Cardiovascular spinal reflex activity in response to cutaneous surgical stimuli was first published as a case report by Wetzel et al. [41. They also noted this phenomenon in a retrospective analysis of anaesthesia protocols. In the two cases presented here, on the other hand, brain death was documented by cerebral angiography and the influence of vasoactive drugs was completely rule out in case 1. The spinal cord distal to a lesion is well known to become highly excitable in patients with spinal cord injury with a dissemination of the reflex process along the spinal cord. Autonomic hypertension in paraplegic patients is associated with elevated circulating plasma norepinephfine, but not epinephrine, suggesting that the hypertension is due to sympathetic hyperactivity and not the release of vasopressor hormones [10]. The impressive increase in plasma epinephrine during the reflex activity in the two cases presented here indicates involvement of the adrenal medulla in the reflex path. It remains to be clarified why this reflex only occurs in a few organ donors (in this study 6.6%). The hemodynamic behavior of most brain-dead patients is characterized by arterial hypotension. The loss of brain-stem located vasomotor control leads to a loss in systemic vascular resistance and to left heart dysfunction [1 iI. Thus, the unexpected occurrence of hypertensive responses to surgical stimuli in organ donors regularly causes a great deal of uneasiness among the medical personnel dealing with them. This report of two cases with angiographically confirmed brain death presents evidence for the spinal origin of the marked hypertensive response to surgery in brain-dead organ donors. Cardiovascular spinal reflex activity does not invalidate the current criteria for diagnosis of brain death.

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Fig. 1. a Systolic and diastolic arterial blood pressure (BPs/cO and heart rate (/) of patient 1 during intensive care and organ harvesting. b Plasma catecholamine concentrations during the study period: ArE = norepinephrine, E = epinephrine, DA = dopamine

1. Ivan LP (1973) Spinal reflexes in cerebral death. Neurology 23:650-652 2. Jorgensen EO (1973) Spinal man after brain death. Acta Neurochir (Wien) 28:259-273

495 3. Turmel A, Roux A, Bojanowski MW (1991) Spinal man after declaration of brain death. Neurosurgery 28:298-301 4. Wetzel RC, Setzer N, Stiff JL, Rogers MC (1985) Hemodynamic responses in brain dead organ donor patients. Anesth Analg 64:125-128 5. Larson MD (1985) Surgically induced hypertension in brain dead patients. Anesth Analg: 1030 6. Conci F, Procacaccio F, Arosio M, Boselli L (t986) Viscero-somatic and viscero-visceral reflexes in brain death. J Neurol Neurosurg Psychiatry 49:695-698 7. Wissenschaftlicher Beirat der Bundes~trztekammer (1986) Kriterien des Hirntodes. Dtsch Arztebl 43:2940-2946 8. Zimmermann J, Dennhardt R, Gramm H-J (1991) Measurement of plasma catecholamines by high-performance liquid chromatography with electrochemical detection in intensive care patients after dobutarnine infusion. J Chromatogr 567:240-247 9. Dowman CBB, McSwiney BA (1946) Reflexes elicited by visceral stimulation in the acute spinal animal. J Physiol (Lond) 105:80-:94

10. Naftchi NE, Wooten GF, Lowman EW, Axelrod J (1974) Relationship between serum dopamine-B-hydroxylase activity, catecholamine metabolism, and hemodynamic changes during paroxysmal hypertension in quadriplegia. Circ Res 35:850-861 11. Nishimura N and Miyata Y (1984) Cardiovascular changes in the terminal stage of disease. Resuscitation 12:175-180

Dr. H.-J. Gramm Department of Anesthesiology and Critical Care Medicine Steglitz Medical Center Free University of Berlin Hindenburgdamm 30 1000 Berlin 45 FRG