1142
pethidine blood concentrations did eventually approach "analgesic" levels in some patients by 30-40 min post injection. This resulted in no increase in analgesia and a transistory (10-15 min) mild sedation. In two patients, intravenous injection of naloxone 0.4 mg was followed by immediate reversal of sedation, with no change in level of analgesia: 30 min later there was a reduction but not a reversal of analgesic effect. These data strongly suggest that the initial analgesic effect of the high doses of epidural pethidine was due to a spinal action. At later stages (40-60 min post injection) analgesia may have resulted from a combination of a spinal action and the central-nervous-system effects associated with blood-borne pethidine. However, the reversal of sedative effects of pethidine by intravenous naloxone with no immediate change in analgesic effect favours the predominant action being on the spinal cord. Yaksh and Rudy have shown that naloxone administered directly into the C.S.F. rapidly antagonises the analgesic effect of subarachnoid morphine in animals. The lag-time between naloxone administration and antagonism of analgesia in our studies was probably due to the slow rate of naloxone delivery caused by the lower perfusion of the spinal cord compared to the brain. Neurological examination before and after epidural pethidine revealed no detectable change in sensory, motor, or sympathetic function. Absence of motor blockade was further illustrated by the ability of patients to ambulate within 30 min of injection. Absence of sympathetic block was confirmed by After 100 mg doses,
retention of
a
normal cobalt-blue
sweat
testS and absence of
postural hypotension after epidural pethidine. Venous occlusion skin plethysmography in the feet showed no evidence of increased blood-flow, and a normal ice responses was retained. In contrast
subsequent injection of 10 ml of local anaesthetic
resulted in at least a four-fold increase in abolition of the response to ice, indicating complete sympathetic blockade in lower limbs. Although the local anaesthetic injection was effective in relieving pain, this was accompanied by sympathetic, sensory, and motor blockade. None of the patients with chronic pain obtained complete pain relief with a control injection of saline whereas all obtained complete pain relief with epidural pethidine. These pharmacokinetic and neurological data provide strong support for a selective spinal analgesic action of epidural pethidine in man. The absence of changes in sensory, sympathetic, and motor function indicates that this form of analgesia may have considerable advantages for relief of severe acute and chronic pain in man.
(0.5% bupivacaine)
foot blood-flow and
an
tion,
motor
function, heart-rate, arterial pressure, and respira-
tory frequency. Sedation was moderate or absent. The potent and prolonged analgesia without central depreswe observed with intrathecal morphine accords with experimental data’ and with a preliminary report in man.2 The detectable thoracic upper level of analgesia we observed has not been previously reported in man and strongly supports a direct effect of narcotics, when given intrathecally, on the spinal cord. It would be interesting to know if Behar et al. have observed such a level of analgesia after epidural morphine. The delay of onset of analgesia we observed with 20 mg intrathecal morphine was longer than the delay recorded by Behar et al. with 2 mg epidural morphine (26 and 3 min, respectively). Such a rapid onset of analgesia may be due to the diffusion of morphine from the hypervascularised epidural
sion that
space into blood.
Nevertheless, we do agree with Behar et al. when they suggest that the unusual prolonged analgesia observed after a single administration of epidural morphine supports the hypothesis of a direct spinal action. K. SAMII J. FERET
Département d’Anesthésie-Réanimation, Hôpital Pitié-Salpêtrière, 75013 Paris, France
A. HARARI P. VIARS
SAFE EXPIRATORY VALVE FOR ANÆSTHESIA AND ARTIFICIAL VENTILATION
SIR,-Dr Wright (April 21, p. 854) offers anaesthetists the of simplicity. He expresses an enviable degree of confidence in his device when he describes it as "safe". When hand ventilation against high airway resistance is necessary, Wright offers two suggestion, one of which involves removing the valve from the system. I think I can accept the logic of his recommendation but I am opposed instinctively to the temporary removal of a safety device ("where did I put it?") when conditions are adverse. The alternative is to modify the valve to permit high-pressure ventilation by the finger (whose?). I find this suggestion even less acceptable because under difficult circumstances there is not usually a finger to
genius
-
Department of Anæsthesia and Intensive Care, School of Medicine, Flinders University of South Australia, Bedford Park, South Australia 5042
M. J. COUSINS L. E. MATHER C. J. GLYNN P. R. WILSON J. R. GRAHAM
SiR,—Dr Behar and colleagues report an analgesic effect of epidural morphine and suggest a direct spinal action of narcotic analgesics. We would like to report our experience of intrathecal morphine. Ten patients were given 20 mg morphine intrathecally as a hypertonic solution (morphine 1% and dextrose 15%). Immediately after the injection the patients were put in a 40 degree head-up position. Over a 48 h period intensity of pain (scored 0-5), level of analgesia by pinprick, fine sensation (epicritic sensibility), motor function, heart-rate, arterial pressure, respiratory frequency, and degree of sedation were recorded. Analgesia appeared at 26±4 min (mean±s.E.M.), reached a peak at 1 h, and disappeared at 27±2 h. The initial pain, which was severe (score 5), decreased to score 0 or 1 in all patients. The upper level of analgesia was easily detectable and ranged from Tl to T6. No change was observed in fine sensa8.
Cousins, M. J., and others. ibid. (in the press).
spare.
Wright’s modification of the standard Heidbrink valve is readily available, inexpensive, and effective. NeverthelessI should prefer a device that will permit ventilation at 6 kPa (just in excess of the standard 2 litre bag pressure limit) for short periods, the pressure automatically reverting to 3 kPa over several minutes after the higher pressure requirements have ceased. I have in mind a two-pressure setting device which could be "wound up" to the higher pressure and which would automatically "wind down" to the lower. If the need for high pressure persists the valve could be re-wound periodically, While the need for high-pressure ventilation is not an everyday occurrence it is not rare-perhaps, one case a month in busy general anaesthetic practice. Such cases are common in thoracic anaesthesia. Department of Anæsthesia,
Royal Free Hospital, London NW3 2QG
T. HILARY HOWELLS
FAST GLYCOSYLATION OF HÆMOGLOBIN
SIR,-Dr Welch (March 31, p. 728) and Dr Leslie and his colleagues (April 7, p. 773), commenting on our finding (March 17, p. 603) of fast glycosylation and de-glycosylation of haemoglobin in diabetics, maintain the view that the sessment
of
true, but
our
of
glycosylated haemoglobin is an aid to the aslong-term diabetic control. This might well be
measurement
critics
seem to
miss
our
point, which was that this
1. Yaksh, T. L., Rudy, T. A. Science, 1976, 192, 1352. 2. Wang, Y. K. Ann. Anesth. fr. 1978, 19, 371.
1143 has not yet been proved. Since there are considerable clinical and economic implications, the difference of opinion is not merely academic. Correct clinical use of any laboratory test requires that all possible problems in measuring and interpreting the variable in question be resolved. This applies to measurement of both HbA’e and HbA1. Rapid fluctuations in glycosylation of hxmoglobin could well be a pitfall of considerable importance in the assessment of diabetic control. Published work (and our own observations) does indeed demonstrate a correlation between diabetic control and HbAle or HbAI levels in groups of patients. However, to be useful to the clinician a good correlation must hold for individuals and for diabetics who are not in extreme states of very good or very bad regulation. To our knowledge, such a correlation has not been reported, and preliminary results from our clinic are not
tion of normal red blood-cells in a mixture of trace amounts of 14C-glucose and 40 mmol/1 unlabelled glucose. After subsequent incubation in glucose-free medium this radioactive peak disappeared. Furthermore, after incubation of normal red blood-cells in saline (37°C, 24 h) with trace amounts of 14C-glucose, radioactivity was eluted in the main HbA1e peak indicating that 14C-glucose was incorporated in h2emoglobin Ale although a net decrease was measured. This is further evidence that glucose in the HbA1e molecule is interchangeable with free glucose. Until methodological studies in depth and better clinical studies of the usefulness of HbA1e and HbA1 in assessment of long-term diabetic control in ordinary diabetic outpatients are available, scepticism is still justified. P. AABY SVENDSEN J. SANDAHL CHRISTIANSEN A. RENARD ANDERSEN B. WELINDER J. NERUP
convincing. Leslie et al. report on changes in HbAI during the first weeks of treatment in newly diagnosed diabetics. Decreases in HbAI of 5-24% (mean 15%) did occur during the first week. If we ignore the unlikely possibility that these patients had a considerable degree of haemolysis, this finding can be explained only by rather rapid intraerythrocytic deglycosylation. We are unable to confirm Welch’s report on the production of stable HbAI after incubation of normal red blood-cells in 100 mmol/1 glucose and subsequent washing in glucose-free medium and on the stability of HbAI in diabetic’s red bloodcells during washing in glucose-free saline. In red blood-cells from four controls the mean HbAle rose from 5.16% to 9.18% after 7 h incubation in 100 mmol/1 glucose in saline at 37°C but decreased to 5.4% after another 17 h incubation in glucosefree saline at 37°C. Thus only 6.2% of the rapidly formed HbAle remained in the cells. This is in contrast to 79-4% reported by Welch for HbAI. In our experiments changes in HbAla+b fraction were insignificant. Further, in blood from eight diabetics we found that the level of HbAle decreased from after incubation in 6 mean 9.74% to 8.81% (2p
pethidine blood concentrations did eventually approach "analgesic" levels in some patients by 30-40 min post injection. This resulted in no increase in analgesia and a transistory (10-15 min) mild sedation. In two patients, intravenous injection of naloxone 0.4 mg was followed by immediate reversal of sedation, with no change in level of analgesia: 30 min later there was a reduction but not a reversal of analgesic effect. These data strongly suggest that the initial analgesic effect of the high doses of epidural pethidine was due to a spinal action. At later stages (40-60 min post injection) analgesia may have resulted from a combination of a spinal action and the central-nervous-system effects associated with blood-borne pethidine. However, the reversal of sedative effects of pethidine by intravenous naloxone with no immediate change in analgesic effect favours the predominant action being on the spinal cord. Yaksh and Rudy have shown that naloxone administered directly into the C.S.F. rapidly antagonises the analgesic effect of subarachnoid morphine in animals. The lag-time between naloxone administration and antagonism of analgesia in our studies was probably due to the slow rate of naloxone delivery caused by the lower perfusion of the spinal cord compared to the brain. Neurological examination before and after epidural pethidine revealed no detectable change in sensory, motor, or sympathetic function. Absence of motor blockade was further illustrated by the ability of patients to ambulate within 30 min of injection. Absence of sympathetic block was confirmed by After 100 mg doses,
retention of
a
normal cobalt-blue
sweat
testS and absence of
postural hypotension after epidural pethidine. Venous occlusion skin plethysmography in the feet showed no evidence of increased blood-flow, and a normal ice responses was retained. In contrast
subsequent injection of 10 ml of local anaesthetic
resulted in at least a four-fold increase in abolition of the response to ice, indicating complete sympathetic blockade in lower limbs. Although the local anaesthetic injection was effective in relieving pain, this was accompanied by sympathetic, sensory, and motor blockade. None of the patients with chronic pain obtained complete pain relief with a control injection of saline whereas all obtained complete pain relief with epidural pethidine. These pharmacokinetic and neurological data provide strong support for a selective spinal analgesic action of epidural pethidine in man. The absence of changes in sensory, sympathetic, and motor function indicates that this form of analgesia may have considerable advantages for relief of severe acute and chronic pain in man.
(0.5% bupivacaine)
foot blood-flow and
an
tion,
motor
function, heart-rate, arterial pressure, and respira-
tory frequency. Sedation was moderate or absent. The potent and prolonged analgesia without central depreswe observed with intrathecal morphine accords with experimental data’ and with a preliminary report in man.2 The detectable thoracic upper level of analgesia we observed has not been previously reported in man and strongly supports a direct effect of narcotics, when given intrathecally, on the spinal cord. It would be interesting to know if Behar et al. have observed such a level of analgesia after epidural morphine. The delay of onset of analgesia we observed with 20 mg intrathecal morphine was longer than the delay recorded by Behar et al. with 2 mg epidural morphine (26 and 3 min, respectively). Such a rapid onset of analgesia may be due to the diffusion of morphine from the hypervascularised epidural
sion that
space into blood.
Nevertheless, we do agree with Behar et al. when they suggest that the unusual prolonged analgesia observed after a single administration of epidural morphine supports the hypothesis of a direct spinal action. K. SAMII J. FERET
Département d’Anesthésie-Réanimation, Hôpital Pitié-Salpêtrière, 75013 Paris, France
A. HARARI P. VIARS
SAFE EXPIRATORY VALVE FOR ANÆSTHESIA AND ARTIFICIAL VENTILATION
SIR,-Dr Wright (April 21, p. 854) offers anaesthetists the of simplicity. He expresses an enviable degree of confidence in his device when he describes it as "safe". When hand ventilation against high airway resistance is necessary, Wright offers two suggestion, one of which involves removing the valve from the system. I think I can accept the logic of his recommendation but I am opposed instinctively to the temporary removal of a safety device ("where did I put it?") when conditions are adverse. The alternative is to modify the valve to permit high-pressure ventilation by the finger (whose?). I find this suggestion even less acceptable because under difficult circumstances there is not usually a finger to
genius
-
Department of Anæsthesia and Intensive Care, School of Medicine, Flinders University of South Australia, Bedford Park, South Australia 5042
M. J. COUSINS L. E. MATHER C. J. GLYNN P. R. WILSON J. R. GRAHAM
SiR,—Dr Behar and colleagues report an analgesic effect of epidural morphine and suggest a direct spinal action of narcotic analgesics. We would like to report our experience of intrathecal morphine. Ten patients were given 20 mg morphine intrathecally as a hypertonic solution (morphine 1% and dextrose 15%). Immediately after the injection the patients were put in a 40 degree head-up position. Over a 48 h period intensity of pain (scored 0-5), level of analgesia by pinprick, fine sensation (epicritic sensibility), motor function, heart-rate, arterial pressure, respiratory frequency, and degree of sedation were recorded. Analgesia appeared at 26±4 min (mean±s.E.M.), reached a peak at 1 h, and disappeared at 27±2 h. The initial pain, which was severe (score 5), decreased to score 0 or 1 in all patients. The upper level of analgesia was easily detectable and ranged from Tl to T6. No change was observed in fine sensa8.
Cousins, M. J., and others. ibid. (in the press).
spare.
Wright’s modification of the standard Heidbrink valve is readily available, inexpensive, and effective. NeverthelessI should prefer a device that will permit ventilation at 6 kPa (just in excess of the standard 2 litre bag pressure limit) for short periods, the pressure automatically reverting to 3 kPa over several minutes after the higher pressure requirements have ceased. I have in mind a two-pressure setting device which could be "wound up" to the higher pressure and which would automatically "wind down" to the lower. If the need for high pressure persists the valve could be re-wound periodically, While the need for high-pressure ventilation is not an everyday occurrence it is not rare-perhaps, one case a month in busy general anaesthetic practice. Such cases are common in thoracic anaesthesia. Department of Anæsthesia,
Royal Free Hospital, London NW3 2QG
T. HILARY HOWELLS
FAST GLYCOSYLATION OF HÆMOGLOBIN
SIR,-Dr Welch (March 31, p. 728) and Dr Leslie and his colleagues (April 7, p. 773), commenting on our finding (March 17, p. 603) of fast glycosylation and de-glycosylation of haemoglobin in diabetics, maintain the view that the sessment
of
true, but
our
of
glycosylated haemoglobin is an aid to the aslong-term diabetic control. This might well be
measurement
critics
seem to
miss
our
point, which was that this
1. Yaksh, T. L., Rudy, T. A. Science, 1976, 192, 1352. 2. Wang, Y. K. Ann. Anesth. fr. 1978, 19, 371.
1143 has not yet been proved. Since there are considerable clinical and economic implications, the difference of opinion is not merely academic. Correct clinical use of any laboratory test requires that all possible problems in measuring and interpreting the variable in question be resolved. This applies to measurement of both HbA’e and HbA1. Rapid fluctuations in glycosylation of hxmoglobin could well be a pitfall of considerable importance in the assessment of diabetic control. Published work (and our own observations) does indeed demonstrate a correlation between diabetic control and HbAle or HbAI levels in groups of patients. However, to be useful to the clinician a good correlation must hold for individuals and for diabetics who are not in extreme states of very good or very bad regulation. To our knowledge, such a correlation has not been reported, and preliminary results from our clinic are not
tion of normal red blood-cells in a mixture of trace amounts of 14C-glucose and 40 mmol/1 unlabelled glucose. After subsequent incubation in glucose-free medium this radioactive peak disappeared. Furthermore, after incubation of normal red blood-cells in saline (37°C, 24 h) with trace amounts of 14C-glucose, radioactivity was eluted in the main HbA1e peak indicating that 14C-glucose was incorporated in h2emoglobin Ale although a net decrease was measured. This is further evidence that glucose in the HbA1e molecule is interchangeable with free glucose. Until methodological studies in depth and better clinical studies of the usefulness of HbA1e and HbA1 in assessment of long-term diabetic control in ordinary diabetic outpatients are available, scepticism is still justified. P. AABY SVENDSEN J. SANDAHL CHRISTIANSEN A. RENARD ANDERSEN B. WELINDER J. NERUP
convincing. Leslie et al. report on changes in HbAI during the first weeks of treatment in newly diagnosed diabetics. Decreases in HbAI of 5-24% (mean 15%) did occur during the first week. If we ignore the unlikely possibility that these patients had a considerable degree of haemolysis, this finding can be explained only by rather rapid intraerythrocytic deglycosylation. We are unable to confirm Welch’s report on the production of stable HbAI after incubation of normal red blood-cells in 100 mmol/1 glucose and subsequent washing in glucose-free medium and on the stability of HbAI in diabetic’s red bloodcells during washing in glucose-free saline. In red blood-cells from four controls the mean HbAle rose from 5.16% to 9.18% after 7 h incubation in 100 mmol/1 glucose in saline at 37°C but decreased to 5.4% after another 17 h incubation in glucosefree saline at 37°C. Thus only 6.2% of the rapidly formed HbAle remained in the cells. This is in contrast to 79-4% reported by Welch for HbAI. In our experiments changes in HbAla+b fraction were insignificant. Further, in blood from eight diabetics we found that the level of HbAle decreased from after incubation in 6 mean 9.74% to 8.81% (2p
