373
Measurement of renal blood flow by
magnetic
angiography
resonance
SIR,-An accurate non-invasive method for measurement of renal blood flow (RBF) has long been sought. 1,2 Magnetic resonance angiography (MRA) is a rapidly progressing and promising technique allowing intravascular flow measurements.3-6 In ten volunteers, workers at Stanford University tried to measure RBF directly in renal arteries and veins by cine phase-contrast MRA. They found some correlation between blood flow in the left renal vein multiplied by two and total RBF as measured by p-aminohippuric acid clearance, but no correlation between the MRA measurements of flow in renal arteries and total RBF.7 We have used cardiac-gated cine-phase-contrast MRA, which allows measurement of the change of the rate of intravascular flow during the cardiac cycle, in an experiment aimed at measuring flow in each renal artery separately and at measuring total RBF (as the difference in flow in the aorta above and below the renal arteries). The sum of the two renal artery measurements should equal the difference between supra-aortic and infra-aortic blood flow, and this was so. In the accompanying figure the first two parts show blood flow during the cardiac cycle and the third illustrates the correlation between flow in both renal arteries and the internal control of total RBF measured in the aorta.
The measurements were done in a 49-year-old man (height 177 cm, weight 63 kg). Total RBF is 650 ml/min on the basis of aortic flow measurements and 630 ml/min when the two renal artery measurements are summed. These values are low in the range of what would be expected. Nevertheless the strong correlation between measurement in aorta and renal arteries indicates that MRA might bring within reach a totally non-invasive method for evaluating both total RBF and flow to each kidney during the various phases of the cardiac cycle. The reproducibility and accuracy of measurements in different individuals remains to be evaluated. B. LUNDIN
Department of Radiology, Michigan State University, Clinical Center, East Lansing, Michigan 48824, USA
1. Duarte CG, Elveback LR, Liedtke RR Glomerular filtration rate and renal plasma flow. In. Duarte CG. Renal function tests. Boston Little Brown, 1980: 29-47. 2. Aukland K. Methods for measuring renal blood flow total flow and regional distribution. Ann Rev Physiol 1980; 42: 543-55. 3. Walker MF, Souza SP, Dumoulin CL. Quantitative flow measurements in phase contrast MR angiography. J Comput Assist Tomogr 1988; 12: 304-13. 4. Bendel P, Buonocore E, Bockisch A, Besozzi MC. Blood flow in the carotid arteries: quantification by using phase-sensitive MR imaging AJR 1989, 152: 1307-10. 5. Kondo C, Caputo GR, Semelka R, Foster E, Shimakawa A, Higgins CB. Right and left ventricular stroke volume measurements with velocity-encoded cine MR 6.
Total RBF measured in Ao Total RBF measured in RA’s
0
R. MEYER T. COOPER E. J. POTCHEN
imaging. AJR 1991, 157: 9-16. Caputo GR, Kondo C, Masui T, et al. Right and left lung perfusion: in vitro and in vivo validation with oblique-angle, velocity encoded cine MR imaging. Radiology 1991; 180: 693-98 G, Noorbehesht B, Pelc N, et al. Renal blood flow measurements using phase-contrast cine MRI Presentation to 10th annual meeting of SMAM (1991): abstr vol II, 966
7. Sommer
Statusepilepticus complicating intrathecal
Time (ms) 0 .
Ao above RA’s Ao below RA’s
v
Right RA
A
Left RA
baclofen overdose SIR,-Intrathecal baclofen is used to treat supraspinal spasticity secondary to severe brain injury.’ To achieve a response daily doses up to 900 ltg have been given, increasing the risk of side-effects. One unwanted effect, with serious implications for patients with supraspinal spasticity secondary to brain injury, is a lowering of the seizure threshold; however, this is controversial. Although animal models2 have suggested that the drug has anticonvulsant properties, both anticonvulsant3 and proconvulsant4,5 actions of baclofen have been described after oral administration to man. Electroencephalographic (EEG) disturbances, with periodic delta and triphasic waves and epileptic discharges, have been observed in patients given oral baclofen at therapeutic doses. In 33 reported cases of baclofen overdose, 8 patients had seizures 2-11 h after 150-2000 mg by mouth.’ In 12 published cases of intrathecal overdose, however, seizures have not been reported,’ and Dralle et al8 have reported an antiepileptic effect of intrathecal baclofen in a child with intractable
epilepsy.
432
CJU
Time
0-to
750
.J/
(ms)
Y = 4.67 + 0.53X Correlation Coefficient: 0.85
v.
c..n L.
.u.v
I.,
.
. .
GV.V 20.0
22.3 GG.J
GJ.V 23.0
Aortic Measurement
(mi/sec) Blood flow during cardiac cycle (upper and middle) and correlation between renal artery and aortic measurements.
Baclofen, when administered at a dose of about 1 µg into the lamina IV-V of the rat sensorimotor cortex caused simple focal seizures with a mean latency of 17 min and a duration of more than 5 h.9 20 µg injected into the 3rd or 4th ventricle elicited generalised seizures and postictal depression. Rat models5 demonstrated a net pro-epileptic concentration-dependent effect of baclofen in the dentate gyrus. We report here a case of status epilepticus after intrathecal baclofen overdose. Spasticity in a 16-year-old patient with tetraparesis due to brain injury did not respond to oral antispastic treatment but did respond to intrathecal baclofen delivered through an implanted delivery system (Cordis ’SECOR’) in daily doses of 200-400 µg. Focal motor seizures, first occurring 2 months after the head injury, were well controlled by 300 mg phenytoin daily. While the drug reservoir was being refilled 10 mg baclofen was administered into the intrathecal space when the reservoir was accidentally punctured. 50 min later the patient was somnolent; after 80 min flaccid muscle tone developed with absent tendon reflexes, nystagmus, and respiratory depression requiring artificial ventilation. Intravenous physostigmine7 (4 mg in 3 min then 2 mg per hour to a total of 14 mg) had no effect. 6 h after the baclofen overdose the patient had focal motor seizures with left-sided clonic motor activity followed by secondary generalisation. This was controlled in 90 min. 45 min later an EEG was abnormal with
374
2-3 Hz activity and spikes and sharp waves over the right hemisphere. 25 h post-intoxication the EEG was very abnormal with diffuse 1-5-3 Hz activity intermingled with spikes every 4-5 s. At 31 h the EEG was still abnormal but after 5 days the EEG returned to the pre-intoxication patterns, being moderately abnormal with slowing of occipital basic rhythms (4-7 Hz) and continuous 2-3 Hz activity over the right hemisphere with rhythmic and sharp components. The patient was then discharged from intensive care in a clinical state comparable with that before the overdose. 8 h after the accident the drug reservoir was removed and 30 ml cerebrospinal fluid (CSF) was drained out. Five samples each were assayed for baclofen and the mean (SD) concentration was 4-27 (0-40) µg/ml. Simultaneous blood samples contained no trace of the drug. In this case, an intrathecal baclofen overdose was followed by a focal seizure and then secondary generalisation with a latency of 6 h. Clinical and EEG findings suggest seizure activity, generated in a previously active right hemisphere focus, via the mechanism demonstrated by Mott et al.5 The half-life of physostigmine is only 25-30 min and this drug is not likely to have been responsible for the seizure. In contrast to the experience of Muller Schwefe and Penn’ physostigmine did not reverse the symptoms of baclofen overdose. Intrathecal (and oral) balcofen overdoses necessitate immediate artificial ventilation and intensive monitoring. An increased risk of seizures should be born in mind in patients given intrathecal baclofen, and EEG monitoring is advisable, especially in those with supraspinal spasticity who may need larger doses than those with spinal spasticity. In epileptic patients taking baclofen, antiepileptic drug serum concentrations should be checked and a reduction of antiepileptic drug doses8 should be avoided. L. SALTUARI M. J. MAROSI
Department of Neurorehabilitation and Department for Seizure Disorders and EEG, University Hospital for Neurology,
M. KOFLER G. BAUER
A-6020 Innsbruck, Austria
1. Saltuari L, Schmutzhard K, Kofler M, Baumgartner H, Aichner F, Gerstenbrand F. Intrathecal baclofen for intractable spasticity due to severe brain injury. Lancet 1989; ii: 503-04. 2. Olpe HR, Demieville H, Baltzer V, et al. The biologic activity of D- and L-baclofen. Eur Pharmacol J 1978; 52: 133-36. 3. Terrence CF, Fromm GH, Matei SR. Baclofen: its effect on seizure frequency. Arch Neurol 1983; 40: 28-29. 4. Pinto O, Polikar M, Loustalot P. A review of clinical trials with lioresal. In Birkmayer W, ed. Spasticity: a topical survey. Bern: Hans Huber, 1972. 5. Mott DD, Bragdon AC, Lewis DV, Wilson WA. Baclofen has a proepileptic effect in the dentate gyrus of rats. J Pharmacol Exp Ther 1989; 249: 721-25. 6. Nugent S, Katz D, Little TE. Baclofen overdose with cardiac conduction abnormalities: case report and review of the literature. Clin Toxicol 1986; 24: 321-28. 7. Muller Schwefe G, Penn RD. Physostigmin in the treatment of intrathecal baclofen overdose. J Neurosurg 1989; 71:273-75. 8. Dralle D, Neuhauser G, Tann JC. Intrathecal baclofen for cerebral spasticity. Lancet 1989; ii: 976. 9. Van Rijn CM, Van Berlo MJ, Feenstra MG, Schoofs ML, Hommes OR. R( -) baclofen: focal epilepsy after intrathecal administration in the rat. Epilepsy Res 1987; 1: 321-27.
Liposomal amphotericin SIR,-Dr Hudson and colleagues (Dec 14,
p
B 1534) reported
of focal hepatic candidosis with ’AmBisome’, commercially available liposomal amphotericin B preparation. We have used this product for more than 3 years for invasive fungal infections in bone marrow and organ transplant recipients.1 Because of toxicity it is not possible to give therapeutic doses of conventional amphotericin B to transplant recipients who are on cyclosporin or other nephrotoxic drugs, but with ambisome daily doses of up to 3-5 mg/kg are generally well tolerated.1,2 By contrast, with amphotericin B, acute toxicity with chills and fever occurs in almost all patients, even at doses as low as 03 mg/kg, limiting the value of this preparation. Of 10 transplant recipients with proven or presumed invasive fungal infections treated with ambisome, 1 did not respond, compared with 6 necropsy-proven fatal fungal infections in 10 retrospective controls treated with conventional amphotericin. In each group there were 8 bone marrow recipients and 1 kidney and 1 liver graft recipient. We have summarised the experience with 126 patients treated for 137 episodes of fungal infection with ambisome in forty-three
successful the first
treatment
hospitals world-wide. These patients had malignant diseases (72), organ transplants (17), immunological disorders (20) (12 with AIDS), or other conditions. 64 in whom fungi were identified from a deep site by culture and/or microscopy were treated for at least 8 days with ambisome. 26 of 29 patients with aspergillosis had infection in the lungs; of 25 cases of candida infection 13 were in blood, 4 were hepatic, and 4 were abdominal; the 7 cases of Cryptococcus neoformans had positive cultures from cerebrospinal fluid; the other 3 had pulmonary mucormycosis, pulmonary coccidiodomycosis, and Trichosporon capitatum septicaemia. Ambisome was given for 8-97 days (29 days on average). Ambisome was administered at doses of 0-9-4 mg/kg daily (mean 24) with cumulative doses of 0-6-16-8 g (3-5). Of the 64 patients with proven invasive fungal infections, 37 (58%) were cured, defmed as disappearance of all symptoms, and in 35 fungi were found to have been eradicated on follow-up examinations. The cure rate was better for candida infection than for aspergillus infection (76% vs 31 %, p < 0-01) perhaps because most aspergillus infections affected the lung, in which low concentrations of amphotericin B have been found at necropsy.3 Pulmonary infections may require higher doses. Liver and spleen contain high concentrations of amphotericin B (93-291 mg/kg) and this may explain the good response of hepatic candidosis in Hudson and colleagues’ patient. Liposomes may be entrapped in the reticuloendothelial system. Electron microscopy shows that liposomes (stained with gold) enter the cytoplasm of fungusinfected peritoneal macrophages.4 Some liposomes were in intracellular vacuoles in direct contact with the fungal cell wall. Thus, amphotericin B in the liposomes could damage the fungi. Hudson and colleagues’ patient had not responded to conventional amphotericin B and in our experience 16/20 patients in whom previous amphotericin B had failed were cured by or responded to ambisome. Because of difficulty in diagnosing invasive fungal infections, ambisome may be suitable for prophylactic use or for treatment of fever of unknown origin that does not respond to antibiotics in patients at high risk of invasive fungal infections. We are nearing the end of a double-blind placebo-controlled trial of ambisome prophylaxis in bone marrow and liver transplant recipients. Ambisome is expensive but it could prove to be a breakthrough in the treatment of invasive fungal infections in
immunocompromised patients. Department of Transplantation Surgery and Chemical Immunology, Karolinksa Institute,
Huddinge Hospital, S-141 86 Huddinge, Sweden
OLLE RINGDÉN JAN TOLLEMAR GUNNAR TYDÉN
1.
Tollemar J, Ringdén O, Tydén G. Liposomal amphotericin-B (AmBisome) treatment in solid organ and bone marrow transplant recipients: efficacy and safety evaluation. Clin Transplant 1990; 4: 167-75. 2. Meunier F, Prentice HG, Ringdén O. Liposomal amphotericin B (AmBisome): safety data from a phase II/III clinical trial. J Amtimicrob Chemother 1991; 28 (suppl B): 83-91
Ringdén O, Meunier F, Tollemar J, et al. Efficacy of amphotericin B encapsulated in liposomes (AmBisome) in the treatment of invasive fungal infections in immunocompromised patients. J Antimicrob Chemother 1991; 28 (suppl B): 73-82. 4. Junge MM, Adler-Moore JP. Electron microscopic study of infected macrophages treated with free and liposome associated amphotericin B. Abstr Am Soc Microbiol 1986; 405: (F-47). 3.
SIR,-Systemic candidosis is a serious, often fatal, infection in very-low-birthweight babies. Liposomal amphotericin B (’AmBisone’), has been used in the treatment of systemic candidosis in a 9-month-old transplant recipient;1 we report the use of this formulation in a much younger baby. A baby delivered by emergency caesarean section at 28 weeks’ required ventilation for respiratory distress syndrome. Routine cultures were negative except for gastric aspirate and urine which grew Candida glabrata. Oral nystatin was given. On day 4 a persistent metabolic acidosis developed with increased ventilatory requirements. Cefotaxime, amphotericin B (1 mg/kg every 24 h), and flucytosine (100 mg/kg every 24 h) were started after a full screen for sepsis. All cultures were negative after 2 days and the antifungal agents were discontinued. The baby also had thrombocytopenia, conjugated hyperbilirubinaemia, and hepatosplenomegaly. The baby deteriorated on day 8. C glabrata was eventually isolated from blood on day 13, and amphotericin B
Measurement of renal blood flow by
magnetic
angiography
resonance
SIR,-An accurate non-invasive method for measurement of renal blood flow (RBF) has long been sought. 1,2 Magnetic resonance angiography (MRA) is a rapidly progressing and promising technique allowing intravascular flow measurements.3-6 In ten volunteers, workers at Stanford University tried to measure RBF directly in renal arteries and veins by cine phase-contrast MRA. They found some correlation between blood flow in the left renal vein multiplied by two and total RBF as measured by p-aminohippuric acid clearance, but no correlation between the MRA measurements of flow in renal arteries and total RBF.7 We have used cardiac-gated cine-phase-contrast MRA, which allows measurement of the change of the rate of intravascular flow during the cardiac cycle, in an experiment aimed at measuring flow in each renal artery separately and at measuring total RBF (as the difference in flow in the aorta above and below the renal arteries). The sum of the two renal artery measurements should equal the difference between supra-aortic and infra-aortic blood flow, and this was so. In the accompanying figure the first two parts show blood flow during the cardiac cycle and the third illustrates the correlation between flow in both renal arteries and the internal control of total RBF measured in the aorta.
The measurements were done in a 49-year-old man (height 177 cm, weight 63 kg). Total RBF is 650 ml/min on the basis of aortic flow measurements and 630 ml/min when the two renal artery measurements are summed. These values are low in the range of what would be expected. Nevertheless the strong correlation between measurement in aorta and renal arteries indicates that MRA might bring within reach a totally non-invasive method for evaluating both total RBF and flow to each kidney during the various phases of the cardiac cycle. The reproducibility and accuracy of measurements in different individuals remains to be evaluated. B. LUNDIN
Department of Radiology, Michigan State University, Clinical Center, East Lansing, Michigan 48824, USA
1. Duarte CG, Elveback LR, Liedtke RR Glomerular filtration rate and renal plasma flow. In. Duarte CG. Renal function tests. Boston Little Brown, 1980: 29-47. 2. Aukland K. Methods for measuring renal blood flow total flow and regional distribution. Ann Rev Physiol 1980; 42: 543-55. 3. Walker MF, Souza SP, Dumoulin CL. Quantitative flow measurements in phase contrast MR angiography. J Comput Assist Tomogr 1988; 12: 304-13. 4. Bendel P, Buonocore E, Bockisch A, Besozzi MC. Blood flow in the carotid arteries: quantification by using phase-sensitive MR imaging AJR 1989, 152: 1307-10. 5. Kondo C, Caputo GR, Semelka R, Foster E, Shimakawa A, Higgins CB. Right and left ventricular stroke volume measurements with velocity-encoded cine MR 6.
Total RBF measured in Ao Total RBF measured in RA’s
0
R. MEYER T. COOPER E. J. POTCHEN
imaging. AJR 1991, 157: 9-16. Caputo GR, Kondo C, Masui T, et al. Right and left lung perfusion: in vitro and in vivo validation with oblique-angle, velocity encoded cine MR imaging. Radiology 1991; 180: 693-98 G, Noorbehesht B, Pelc N, et al. Renal blood flow measurements using phase-contrast cine MRI Presentation to 10th annual meeting of SMAM (1991): abstr vol II, 966
7. Sommer
Statusepilepticus complicating intrathecal
Time (ms) 0 .
Ao above RA’s Ao below RA’s
v
Right RA
A
Left RA
baclofen overdose SIR,-Intrathecal baclofen is used to treat supraspinal spasticity secondary to severe brain injury.’ To achieve a response daily doses up to 900 ltg have been given, increasing the risk of side-effects. One unwanted effect, with serious implications for patients with supraspinal spasticity secondary to brain injury, is a lowering of the seizure threshold; however, this is controversial. Although animal models2 have suggested that the drug has anticonvulsant properties, both anticonvulsant3 and proconvulsant4,5 actions of baclofen have been described after oral administration to man. Electroencephalographic (EEG) disturbances, with periodic delta and triphasic waves and epileptic discharges, have been observed in patients given oral baclofen at therapeutic doses. In 33 reported cases of baclofen overdose, 8 patients had seizures 2-11 h after 150-2000 mg by mouth.’ In 12 published cases of intrathecal overdose, however, seizures have not been reported,’ and Dralle et al8 have reported an antiepileptic effect of intrathecal baclofen in a child with intractable
epilepsy.
432
CJU
Time
0-to
750
.J/
(ms)
Y = 4.67 + 0.53X Correlation Coefficient: 0.85
v.
c..n L.
.u.v
I.,
.
. .
GV.V 20.0
22.3 GG.J
GJ.V 23.0
Aortic Measurement
(mi/sec) Blood flow during cardiac cycle (upper and middle) and correlation between renal artery and aortic measurements.
Baclofen, when administered at a dose of about 1 µg into the lamina IV-V of the rat sensorimotor cortex caused simple focal seizures with a mean latency of 17 min and a duration of more than 5 h.9 20 µg injected into the 3rd or 4th ventricle elicited generalised seizures and postictal depression. Rat models5 demonstrated a net pro-epileptic concentration-dependent effect of baclofen in the dentate gyrus. We report here a case of status epilepticus after intrathecal baclofen overdose. Spasticity in a 16-year-old patient with tetraparesis due to brain injury did not respond to oral antispastic treatment but did respond to intrathecal baclofen delivered through an implanted delivery system (Cordis ’SECOR’) in daily doses of 200-400 µg. Focal motor seizures, first occurring 2 months after the head injury, were well controlled by 300 mg phenytoin daily. While the drug reservoir was being refilled 10 mg baclofen was administered into the intrathecal space when the reservoir was accidentally punctured. 50 min later the patient was somnolent; after 80 min flaccid muscle tone developed with absent tendon reflexes, nystagmus, and respiratory depression requiring artificial ventilation. Intravenous physostigmine7 (4 mg in 3 min then 2 mg per hour to a total of 14 mg) had no effect. 6 h after the baclofen overdose the patient had focal motor seizures with left-sided clonic motor activity followed by secondary generalisation. This was controlled in 90 min. 45 min later an EEG was abnormal with
374
2-3 Hz activity and spikes and sharp waves over the right hemisphere. 25 h post-intoxication the EEG was very abnormal with diffuse 1-5-3 Hz activity intermingled with spikes every 4-5 s. At 31 h the EEG was still abnormal but after 5 days the EEG returned to the pre-intoxication patterns, being moderately abnormal with slowing of occipital basic rhythms (4-7 Hz) and continuous 2-3 Hz activity over the right hemisphere with rhythmic and sharp components. The patient was then discharged from intensive care in a clinical state comparable with that before the overdose. 8 h after the accident the drug reservoir was removed and 30 ml cerebrospinal fluid (CSF) was drained out. Five samples each were assayed for baclofen and the mean (SD) concentration was 4-27 (0-40) µg/ml. Simultaneous blood samples contained no trace of the drug. In this case, an intrathecal baclofen overdose was followed by a focal seizure and then secondary generalisation with a latency of 6 h. Clinical and EEG findings suggest seizure activity, generated in a previously active right hemisphere focus, via the mechanism demonstrated by Mott et al.5 The half-life of physostigmine is only 25-30 min and this drug is not likely to have been responsible for the seizure. In contrast to the experience of Muller Schwefe and Penn’ physostigmine did not reverse the symptoms of baclofen overdose. Intrathecal (and oral) balcofen overdoses necessitate immediate artificial ventilation and intensive monitoring. An increased risk of seizures should be born in mind in patients given intrathecal baclofen, and EEG monitoring is advisable, especially in those with supraspinal spasticity who may need larger doses than those with spinal spasticity. In epileptic patients taking baclofen, antiepileptic drug serum concentrations should be checked and a reduction of antiepileptic drug doses8 should be avoided. L. SALTUARI M. J. MAROSI
Department of Neurorehabilitation and Department for Seizure Disorders and EEG, University Hospital for Neurology,
M. KOFLER G. BAUER
A-6020 Innsbruck, Austria
1. Saltuari L, Schmutzhard K, Kofler M, Baumgartner H, Aichner F, Gerstenbrand F. Intrathecal baclofen for intractable spasticity due to severe brain injury. Lancet 1989; ii: 503-04. 2. Olpe HR, Demieville H, Baltzer V, et al. The biologic activity of D- and L-baclofen. Eur Pharmacol J 1978; 52: 133-36. 3. Terrence CF, Fromm GH, Matei SR. Baclofen: its effect on seizure frequency. Arch Neurol 1983; 40: 28-29. 4. Pinto O, Polikar M, Loustalot P. A review of clinical trials with lioresal. In Birkmayer W, ed. Spasticity: a topical survey. Bern: Hans Huber, 1972. 5. Mott DD, Bragdon AC, Lewis DV, Wilson WA. Baclofen has a proepileptic effect in the dentate gyrus of rats. J Pharmacol Exp Ther 1989; 249: 721-25. 6. Nugent S, Katz D, Little TE. Baclofen overdose with cardiac conduction abnormalities: case report and review of the literature. Clin Toxicol 1986; 24: 321-28. 7. Muller Schwefe G, Penn RD. Physostigmin in the treatment of intrathecal baclofen overdose. J Neurosurg 1989; 71:273-75. 8. Dralle D, Neuhauser G, Tann JC. Intrathecal baclofen for cerebral spasticity. Lancet 1989; ii: 976. 9. Van Rijn CM, Van Berlo MJ, Feenstra MG, Schoofs ML, Hommes OR. R( -) baclofen: focal epilepsy after intrathecal administration in the rat. Epilepsy Res 1987; 1: 321-27.
Liposomal amphotericin SIR,-Dr Hudson and colleagues (Dec 14,
p
B 1534) reported
of focal hepatic candidosis with ’AmBisome’, commercially available liposomal amphotericin B preparation. We have used this product for more than 3 years for invasive fungal infections in bone marrow and organ transplant recipients.1 Because of toxicity it is not possible to give therapeutic doses of conventional amphotericin B to transplant recipients who are on cyclosporin or other nephrotoxic drugs, but with ambisome daily doses of up to 3-5 mg/kg are generally well tolerated.1,2 By contrast, with amphotericin B, acute toxicity with chills and fever occurs in almost all patients, even at doses as low as 03 mg/kg, limiting the value of this preparation. Of 10 transplant recipients with proven or presumed invasive fungal infections treated with ambisome, 1 did not respond, compared with 6 necropsy-proven fatal fungal infections in 10 retrospective controls treated with conventional amphotericin. In each group there were 8 bone marrow recipients and 1 kidney and 1 liver graft recipient. We have summarised the experience with 126 patients treated for 137 episodes of fungal infection with ambisome in forty-three
successful the first
treatment
hospitals world-wide. These patients had malignant diseases (72), organ transplants (17), immunological disorders (20) (12 with AIDS), or other conditions. 64 in whom fungi were identified from a deep site by culture and/or microscopy were treated for at least 8 days with ambisome. 26 of 29 patients with aspergillosis had infection in the lungs; of 25 cases of candida infection 13 were in blood, 4 were hepatic, and 4 were abdominal; the 7 cases of Cryptococcus neoformans had positive cultures from cerebrospinal fluid; the other 3 had pulmonary mucormycosis, pulmonary coccidiodomycosis, and Trichosporon capitatum septicaemia. Ambisome was given for 8-97 days (29 days on average). Ambisome was administered at doses of 0-9-4 mg/kg daily (mean 24) with cumulative doses of 0-6-16-8 g (3-5). Of the 64 patients with proven invasive fungal infections, 37 (58%) were cured, defmed as disappearance of all symptoms, and in 35 fungi were found to have been eradicated on follow-up examinations. The cure rate was better for candida infection than for aspergillus infection (76% vs 31 %, p < 0-01) perhaps because most aspergillus infections affected the lung, in which low concentrations of amphotericin B have been found at necropsy.3 Pulmonary infections may require higher doses. Liver and spleen contain high concentrations of amphotericin B (93-291 mg/kg) and this may explain the good response of hepatic candidosis in Hudson and colleagues’ patient. Liposomes may be entrapped in the reticuloendothelial system. Electron microscopy shows that liposomes (stained with gold) enter the cytoplasm of fungusinfected peritoneal macrophages.4 Some liposomes were in intracellular vacuoles in direct contact with the fungal cell wall. Thus, amphotericin B in the liposomes could damage the fungi. Hudson and colleagues’ patient had not responded to conventional amphotericin B and in our experience 16/20 patients in whom previous amphotericin B had failed were cured by or responded to ambisome. Because of difficulty in diagnosing invasive fungal infections, ambisome may be suitable for prophylactic use or for treatment of fever of unknown origin that does not respond to antibiotics in patients at high risk of invasive fungal infections. We are nearing the end of a double-blind placebo-controlled trial of ambisome prophylaxis in bone marrow and liver transplant recipients. Ambisome is expensive but it could prove to be a breakthrough in the treatment of invasive fungal infections in
immunocompromised patients. Department of Transplantation Surgery and Chemical Immunology, Karolinksa Institute,
Huddinge Hospital, S-141 86 Huddinge, Sweden
OLLE RINGDÉN JAN TOLLEMAR GUNNAR TYDÉN
1.
Tollemar J, Ringdén O, Tydén G. Liposomal amphotericin-B (AmBisome) treatment in solid organ and bone marrow transplant recipients: efficacy and safety evaluation. Clin Transplant 1990; 4: 167-75. 2. Meunier F, Prentice HG, Ringdén O. Liposomal amphotericin B (AmBisome): safety data from a phase II/III clinical trial. J Amtimicrob Chemother 1991; 28 (suppl B): 83-91
Ringdén O, Meunier F, Tollemar J, et al. Efficacy of amphotericin B encapsulated in liposomes (AmBisome) in the treatment of invasive fungal infections in immunocompromised patients. J Antimicrob Chemother 1991; 28 (suppl B): 73-82. 4. Junge MM, Adler-Moore JP. Electron microscopic study of infected macrophages treated with free and liposome associated amphotericin B. Abstr Am Soc Microbiol 1986; 405: (F-47). 3.
SIR,-Systemic candidosis is a serious, often fatal, infection in very-low-birthweight babies. Liposomal amphotericin B (’AmBisone’), has been used in the treatment of systemic candidosis in a 9-month-old transplant recipient;1 we report the use of this formulation in a much younger baby. A baby delivered by emergency caesarean section at 28 weeks’ required ventilation for respiratory distress syndrome. Routine cultures were negative except for gastric aspirate and urine which grew Candida glabrata. Oral nystatin was given. On day 4 a persistent metabolic acidosis developed with increased ventilatory requirements. Cefotaxime, amphotericin B (1 mg/kg every 24 h), and flucytosine (100 mg/kg every 24 h) were started after a full screen for sepsis. All cultures were negative after 2 days and the antifungal agents were discontinued. The baby also had thrombocytopenia, conjugated hyperbilirubinaemia, and hepatosplenomegaly. The baby deteriorated on day 8. C glabrata was eventually isolated from blood on day 13, and amphotericin B
