Intensive Care Med (1992) 18:252-253
IntensiveCare Medicine
Correspondence
9 Springer-Verlag 1992
Disturbance of cerebral autoregulation after global ischemia and the stabilizing role of adenosine Dear Sir, In their article on the detrimental effects of low perfusion pressure after global cerebral ischemia Seo et al. were able to show that an irregular distribution of post-ischemic blood flow can enhance brain damage [3]. In an experimental rat model we examined the autoregulatory properties of the cerebral vasculature after global ischemia. An intact autoregulation prevents disruption of the blood brain barrier e.g. during acute hypertension and formation of brain edema. Recent studies have shown that adenosine plays a role in the regulation of cerebral blood flow and the pathophysiology of cerebral reperfusion injury by increasing capillary blood flow and scavenging free radicals [1]. In our experiments we tested the stabilizing effects of HWA 285, a xanthine derivative that increases the extracellular adenosine concentration. In wister rats the break through point was determined where acute norepinephrine induced hypertension caused an increase in cerebral blood flow (rCBF). With an intact autoregulation rCBF remains steady up to 170mmHg despite an increasing mean arterial blood pressure (MABP). Cerebral blood flow was measured with a laser doppler probe directly from the brain surface through a burr hole. The animals were rendered ischemic by four vessel occulusion [2]. Autoregulation was tested in controls and HWA 285 treated animals during reperfusion. There was a steady blood flow in the treatment group compared to controls that showed a sudden increase of rCBF or a hyperperfusion like blood flow pattern, A severe disturbance of autoregulation immediately after declamping could be found. Blood pressure could be stimulated with epinephrine up to 190 mmHg compared to 160 in the treatment group (Fig. 1). An increased extracellular
adenosine concentration turned out to be an essential intracerebral mediator ameliorating the hemodynamic effects of acute hypertension and shifting the dose response curves to the right such that it took more epinephrine to reach a given blood pressure. This might be particularly beneficial during postischemic reperfusion when hypertension can aggravate ischemic brain damage. Clinical studies have to show whether the administration of an adenosine agonist may prevent the hyperperfusion syndrome, a complication that may cause brain edema and even intracerebral hemorrhage after carotid artery endarterectomy. Yours faithfully, R. Kolvenbach, A.T. Nemat and W. Sandmann
References 1. Meno JR, Ngai AC, Winn HR (1991) Adenosine release and changes in pial arteriolar diameter during transient cerebral ischemia and reperfusion. J Cereb Blood Flow Metab 11:986-993 2. Pulsinelli W, Brierley J (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10:267-272 3. Seo K, Ishimaru S, Hossmann K-A (1991) Two stage resuscitation of the cat brain after prolonged cardiac arrest. Intensive Care Med 17:410-418 R. Kolvenbach, Department of Vascular Surgery and Renal Transplantation, Heinrich-Heine University Dfisseldorf, Moorenstrasse 5, 4000 Dfisseldorf, FRG
200 /"
/
/
15o
/
fj?J~
MABP(mmHg)~
,/
+
///
~1-+----+J
~~-~.~ / /
11J" ~
0,01
0,02
0,1 0,2 1 2 10 Norepinephrine dose ~ug/kg i.v.)
20
100
Fig. 1. Mean arterial blood pressure (MABP) and cerebral blood flow (rCBF) in controls and animals treated with the adenosine agonist HWA 285. Each group consisted of 6 wistar rats. The mean values obtained unter an increasing norepinephrine dose are given. Due to postischemie autoregulation disturbance maximum MABP and rCBF are higher in control animals compared to the treatment group. ~-, MABP; +, MABP-HWA, *, rCBF; [2], rCBF-HWA
Can purgation therapy be an adjunct to SDD? Dear Sir, Recent articles describing the potential value of selective decontamination of the digestive tract (SDD) [1] prompts me to ask whether an old Chinese therapy might be a useful adjunct to this modern technique? Controlled clinical trials have shown that SDD is highly effective in preventing the colonization of gram-negative aerobic bacteria (GNAB) in critically ill patients [1] but without any clear-cut improvement in mortality rates. Patients died from multiple system organ failure (MSOF) and "abacterial sepsis" while treated with SDD. Intestinal endotoxemia has been though to contribute to their mortality. One reason this may be occurring is thought the reduction of lower bowel GNAB by SDD is both slow and incomplete. Stress in ICU patients (severe underlying disease and therapy) affects the intestinal flora by causing cessation of the peristaltic movement and decreasing secretion of bile and intestinal juice. Many of therapeutic interventions, such as use of sedatives, antibacterial agents, antacids and H2-receptor antagonists, further encourage indigenous flora and GNAB colonization occurs. Therefore, the purpose of SDD is to improve the indigenous gastronintestinal luminal environment by improving GI tract motility and secretory function, decreasing absorption of intestinal toxins and bacteria translocation. In China, an ancient therapy of digestive tract decontamination without antibiotics has been re-evaluated in the past 30 years with pro-
253 mising resnits [2]. Could the effectiveness of SDD be enhanced by this principle? The purgation method, one of the classic eight therapeutic methods in traditional Chinese medicine, first stated in the third or second century BC, is to relieve constipation, clear stagnation of food or blood and expel internal heat and excessive fluid through purgations by using the laxative herb medicine, such as Rhubarb (Rheum tanguticum). The herbs used for purgation, such as Rhubarb, administered by NG tube in decoction, can reduce body temperature by suppressing the production of PGE and cAMP [3, 4], relieve toxic symptoms, improve GI peristalsis, and relieve abdominal distension in critically ill patients with severe infection [2]. It has also been found that purgatives reduced the incidence of exdotoxemia in acute infection patients [5]. Purgation can stimulate the digestive tract locally and promote intestinal movement. It has been found that electrical activity of colon is excited by rhubarb (Rheum tanguticum) in isolated intestine in rats [6]. The frequency and amplitude of spike potential increases, as does the contraction. This exciting effect of rhubarb on the colon can be blocked by atropine. Some purgatives stimulate the secretion of bile and contraction of the gallbladder. The rhein, the active substance of rhubarb, has also been found to have an activity against Bacteroidesfragilis, a major anaerobic micro-organism in the intestinal flora of humans [7]. Based on the findings and observation that abdominal distension, GI bleeding, iteus and enterobacteriaceae septicemia are frequent in critically ill patients in China, a series of controlled clinical trials using systemic antibiotics and a purgation method have been carried out in infected critically ill patients. Results revealed that this combined therapy significantly decreased the in-hospital mortality rate [4, 5]. Could the purgation principle be useful prophylactically in critically ii1 patients? Yours faithfully, X. Sun
References 1. Reidy J J, Ramsay G (1990) Clinical trials of selective decontamination of the digestive tract: review. Crit Care Med 18:1449-1456 2. Wang BE, Zhao SY (1988) Achievement in the study of therapeutic effect of acute infection with combined traditional Chinese medicine (TCM) and Western medicine (WM). Chinese J Integrated Traditional Western Med 8:142 (Special issue) 3. Guo CY, Wang BE (1986) Temperature-reducing effect of rhubarb and its relation to PGE in the central nervous system. Chinese J Integrated Traditional Western Med 6:106-107 4. Guo CY, Zhao SY, Wang BE et al (1989) Effect of Rheum tanguticum Maxim ex on Ball on cAMP in the central nervous system. Chung Kuo Chung Yao Tsa Chih 14:370-371 5. Chen YW, Wang BE, Zhao SY (1988) Effects of rhubarb and antipneumonia mixture IlI on endotoxemia in acute infection. Chinese J Integrated Traditional Western Med 8:654-657 6. Jin BL, Ma GJ, Wang HX et al (1989) Effects of rhubarb on electricla and contractive activities of the isolated intestine in rats. Chung Kuo Chung Yao Tsa Chih 14:239-241 7. Cyong J, Matsumoto T, Arakawe K et al (1987) Anti-bacteroides fragilis substance from rhubarb. J Ethnopharmacol 19:279-283
X. Sun, MD, Department of ICU Research, The George Washington University Medical Center, 2300 K Street, N.W., Washington DC, 20037, USA
Bradycardias after tracheal disconnection Sir, We were interested in the report by R. Robert and his colleagues [1] showing bradycardias after tracheal disconnection that were unrelated to hypoxia. We have seen three similar arrhythmias with different causes. The first patient was a 28-year-old man admitted after blunt liver trauma. He developed acute renal failure, intra-abdominal sepsis and ARDS. During his recovery (40 days after admission) he had several episodes of sinus bradycardia and asystole after suctioning and even swallowing. This required transvenous veutrieular pacing before discharge. Patient two was a 32-year-old man who had suffered severe multiple trauma to his pelvis and long bones of his legs, that was complicated by deep pelvic sepsis. This needed surgical debridement of his wounds under general anaesthetic. After 6 - 1 0 hr he developed episodes of sinus bradycardia. This resolved spontaneously with no active treatment and was attributed to the release of myocardial toxins from the abscess cavities. The last patient was a 56-year-old man who developed a sinus bradycardia and asystole after being sat out in a chair 3 weeks after liver transplantation. The operation had been needed for alcoholic hepatitis and the course after operation was complicated by encephalopathy and hepatorenal syndrome. The bradycardia responded to atropine. One day later he developed respiratory failure and sepsis for which he was resuscitated and his trachea was reintnbated and ventilatory support restarted. In all these patients the arrhythmia preceded or coincided with the development of sepsis. At the time all 3 were breathing spontaneously, either by mouth or through a tracheostomy, needing moderate oxygen supplementation (FiO2< 0.35). Two of the three were markedly jaundiced with abnormal liver enzymes. All had some degree of renal dysfunction, two patients were receiving continuous haemofiltration at the time. No patient was hyperkalemic. All of the patients are still alive. Although Dr. Robert and his colleagues have shown one cause for bradycardias, others including sepsis and liver dysfunction [2] must also be considered. Yours faithfully, S. Greer, P. Haji-Michael and G .R. Park
References 1. Robert R, Malin F, Bauwens M, Amiel A, Patte D (1991) Severe nonhypoxic bradycardia during disconnection from the ventilator during the recovery phase of ARDS. Intensive Care Med 17:494-496 2. Weston M J, Talbot IC, Howorth PJN, Mant AK, Capildeo R, Williams R (1976) Frequency of arrhythmias and other cardiac abnormalities in fulminant hepatic failure. Br Heart J 38:1179-1188 Dr. G. R. Park, The John Farman ICU, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
IntensiveCare Medicine
Correspondence
9 Springer-Verlag 1992
Disturbance of cerebral autoregulation after global ischemia and the stabilizing role of adenosine Dear Sir, In their article on the detrimental effects of low perfusion pressure after global cerebral ischemia Seo et al. were able to show that an irregular distribution of post-ischemic blood flow can enhance brain damage [3]. In an experimental rat model we examined the autoregulatory properties of the cerebral vasculature after global ischemia. An intact autoregulation prevents disruption of the blood brain barrier e.g. during acute hypertension and formation of brain edema. Recent studies have shown that adenosine plays a role in the regulation of cerebral blood flow and the pathophysiology of cerebral reperfusion injury by increasing capillary blood flow and scavenging free radicals [1]. In our experiments we tested the stabilizing effects of HWA 285, a xanthine derivative that increases the extracellular adenosine concentration. In wister rats the break through point was determined where acute norepinephrine induced hypertension caused an increase in cerebral blood flow (rCBF). With an intact autoregulation rCBF remains steady up to 170mmHg despite an increasing mean arterial blood pressure (MABP). Cerebral blood flow was measured with a laser doppler probe directly from the brain surface through a burr hole. The animals were rendered ischemic by four vessel occulusion [2]. Autoregulation was tested in controls and HWA 285 treated animals during reperfusion. There was a steady blood flow in the treatment group compared to controls that showed a sudden increase of rCBF or a hyperperfusion like blood flow pattern, A severe disturbance of autoregulation immediately after declamping could be found. Blood pressure could be stimulated with epinephrine up to 190 mmHg compared to 160 in the treatment group (Fig. 1). An increased extracellular
adenosine concentration turned out to be an essential intracerebral mediator ameliorating the hemodynamic effects of acute hypertension and shifting the dose response curves to the right such that it took more epinephrine to reach a given blood pressure. This might be particularly beneficial during postischemic reperfusion when hypertension can aggravate ischemic brain damage. Clinical studies have to show whether the administration of an adenosine agonist may prevent the hyperperfusion syndrome, a complication that may cause brain edema and even intracerebral hemorrhage after carotid artery endarterectomy. Yours faithfully, R. Kolvenbach, A.T. Nemat and W. Sandmann
References 1. Meno JR, Ngai AC, Winn HR (1991) Adenosine release and changes in pial arteriolar diameter during transient cerebral ischemia and reperfusion. J Cereb Blood Flow Metab 11:986-993 2. Pulsinelli W, Brierley J (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10:267-272 3. Seo K, Ishimaru S, Hossmann K-A (1991) Two stage resuscitation of the cat brain after prolonged cardiac arrest. Intensive Care Med 17:410-418 R. Kolvenbach, Department of Vascular Surgery and Renal Transplantation, Heinrich-Heine University Dfisseldorf, Moorenstrasse 5, 4000 Dfisseldorf, FRG
200 /"
/
/
15o
/
fj?J~
MABP(mmHg)~
,/
+
///
~1-+----+J
~~-~.~ / /
11J" ~
0,01
0,02
0,1 0,2 1 2 10 Norepinephrine dose ~ug/kg i.v.)
20
100
Fig. 1. Mean arterial blood pressure (MABP) and cerebral blood flow (rCBF) in controls and animals treated with the adenosine agonist HWA 285. Each group consisted of 6 wistar rats. The mean values obtained unter an increasing norepinephrine dose are given. Due to postischemie autoregulation disturbance maximum MABP and rCBF are higher in control animals compared to the treatment group. ~-, MABP; +, MABP-HWA, *, rCBF; [2], rCBF-HWA
Can purgation therapy be an adjunct to SDD? Dear Sir, Recent articles describing the potential value of selective decontamination of the digestive tract (SDD) [1] prompts me to ask whether an old Chinese therapy might be a useful adjunct to this modern technique? Controlled clinical trials have shown that SDD is highly effective in preventing the colonization of gram-negative aerobic bacteria (GNAB) in critically ill patients [1] but without any clear-cut improvement in mortality rates. Patients died from multiple system organ failure (MSOF) and "abacterial sepsis" while treated with SDD. Intestinal endotoxemia has been though to contribute to their mortality. One reason this may be occurring is thought the reduction of lower bowel GNAB by SDD is both slow and incomplete. Stress in ICU patients (severe underlying disease and therapy) affects the intestinal flora by causing cessation of the peristaltic movement and decreasing secretion of bile and intestinal juice. Many of therapeutic interventions, such as use of sedatives, antibacterial agents, antacids and H2-receptor antagonists, further encourage indigenous flora and GNAB colonization occurs. Therefore, the purpose of SDD is to improve the indigenous gastronintestinal luminal environment by improving GI tract motility and secretory function, decreasing absorption of intestinal toxins and bacteria translocation. In China, an ancient therapy of digestive tract decontamination without antibiotics has been re-evaluated in the past 30 years with pro-
253 mising resnits [2]. Could the effectiveness of SDD be enhanced by this principle? The purgation method, one of the classic eight therapeutic methods in traditional Chinese medicine, first stated in the third or second century BC, is to relieve constipation, clear stagnation of food or blood and expel internal heat and excessive fluid through purgations by using the laxative herb medicine, such as Rhubarb (Rheum tanguticum). The herbs used for purgation, such as Rhubarb, administered by NG tube in decoction, can reduce body temperature by suppressing the production of PGE and cAMP [3, 4], relieve toxic symptoms, improve GI peristalsis, and relieve abdominal distension in critically ill patients with severe infection [2]. It has also been found that purgatives reduced the incidence of exdotoxemia in acute infection patients [5]. Purgation can stimulate the digestive tract locally and promote intestinal movement. It has been found that electrical activity of colon is excited by rhubarb (Rheum tanguticum) in isolated intestine in rats [6]. The frequency and amplitude of spike potential increases, as does the contraction. This exciting effect of rhubarb on the colon can be blocked by atropine. Some purgatives stimulate the secretion of bile and contraction of the gallbladder. The rhein, the active substance of rhubarb, has also been found to have an activity against Bacteroidesfragilis, a major anaerobic micro-organism in the intestinal flora of humans [7]. Based on the findings and observation that abdominal distension, GI bleeding, iteus and enterobacteriaceae septicemia are frequent in critically ill patients in China, a series of controlled clinical trials using systemic antibiotics and a purgation method have been carried out in infected critically ill patients. Results revealed that this combined therapy significantly decreased the in-hospital mortality rate [4, 5]. Could the purgation principle be useful prophylactically in critically ii1 patients? Yours faithfully, X. Sun
References 1. Reidy J J, Ramsay G (1990) Clinical trials of selective decontamination of the digestive tract: review. Crit Care Med 18:1449-1456 2. Wang BE, Zhao SY (1988) Achievement in the study of therapeutic effect of acute infection with combined traditional Chinese medicine (TCM) and Western medicine (WM). Chinese J Integrated Traditional Western Med 8:142 (Special issue) 3. Guo CY, Wang BE (1986) Temperature-reducing effect of rhubarb and its relation to PGE in the central nervous system. Chinese J Integrated Traditional Western Med 6:106-107 4. Guo CY, Zhao SY, Wang BE et al (1989) Effect of Rheum tanguticum Maxim ex on Ball on cAMP in the central nervous system. Chung Kuo Chung Yao Tsa Chih 14:370-371 5. Chen YW, Wang BE, Zhao SY (1988) Effects of rhubarb and antipneumonia mixture IlI on endotoxemia in acute infection. Chinese J Integrated Traditional Western Med 8:654-657 6. Jin BL, Ma GJ, Wang HX et al (1989) Effects of rhubarb on electricla and contractive activities of the isolated intestine in rats. Chung Kuo Chung Yao Tsa Chih 14:239-241 7. Cyong J, Matsumoto T, Arakawe K et al (1987) Anti-bacteroides fragilis substance from rhubarb. J Ethnopharmacol 19:279-283
X. Sun, MD, Department of ICU Research, The George Washington University Medical Center, 2300 K Street, N.W., Washington DC, 20037, USA
Bradycardias after tracheal disconnection Sir, We were interested in the report by R. Robert and his colleagues [1] showing bradycardias after tracheal disconnection that were unrelated to hypoxia. We have seen three similar arrhythmias with different causes. The first patient was a 28-year-old man admitted after blunt liver trauma. He developed acute renal failure, intra-abdominal sepsis and ARDS. During his recovery (40 days after admission) he had several episodes of sinus bradycardia and asystole after suctioning and even swallowing. This required transvenous veutrieular pacing before discharge. Patient two was a 32-year-old man who had suffered severe multiple trauma to his pelvis and long bones of his legs, that was complicated by deep pelvic sepsis. This needed surgical debridement of his wounds under general anaesthetic. After 6 - 1 0 hr he developed episodes of sinus bradycardia. This resolved spontaneously with no active treatment and was attributed to the release of myocardial toxins from the abscess cavities. The last patient was a 56-year-old man who developed a sinus bradycardia and asystole after being sat out in a chair 3 weeks after liver transplantation. The operation had been needed for alcoholic hepatitis and the course after operation was complicated by encephalopathy and hepatorenal syndrome. The bradycardia responded to atropine. One day later he developed respiratory failure and sepsis for which he was resuscitated and his trachea was reintnbated and ventilatory support restarted. In all these patients the arrhythmia preceded or coincided with the development of sepsis. At the time all 3 were breathing spontaneously, either by mouth or through a tracheostomy, needing moderate oxygen supplementation (FiO2< 0.35). Two of the three were markedly jaundiced with abnormal liver enzymes. All had some degree of renal dysfunction, two patients were receiving continuous haemofiltration at the time. No patient was hyperkalemic. All of the patients are still alive. Although Dr. Robert and his colleagues have shown one cause for bradycardias, others including sepsis and liver dysfunction [2] must also be considered. Yours faithfully, S. Greer, P. Haji-Michael and G .R. Park
References 1. Robert R, Malin F, Bauwens M, Amiel A, Patte D (1991) Severe nonhypoxic bradycardia during disconnection from the ventilator during the recovery phase of ARDS. Intensive Care Med 17:494-496 2. Weston M J, Talbot IC, Howorth PJN, Mant AK, Capildeo R, Williams R (1976) Frequency of arrhythmias and other cardiac abnormalities in fulminant hepatic failure. Br Heart J 38:1179-1188 Dr. G. R. Park, The John Farman ICU, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
