Postpartum cerebral venous sinus thrombosis following obstetric neuraxial blockade: a literature review with analysis of 58 case reports.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a rare complication of pregnancy. It usually presents with a headache and may mimic a post-dural puncture headache (PDPH) in women who receive a neuraxial block. METHODS: Medline, CINAHL and EMBASE databases were searched to identify postpartum cases of CVST following neuraxial block. The aim was to delineate the characteristics, presentation, investigations, and outcomes of postpartum women who presented with CVST. RESULTS: Forty-nine articles with 58 case reports were identified. Forty-two women (72.4%) had an epidural attempted whilst 16 women (27.6%) received a spinal anaesthetic. Accidental dural puncture (ADP) was reported in 17 women (40.5%). Headache was the presenting symptom in 57 women (98.3%); 26 women (44.8%) also experienced seizures. Post-dural puncture headache was reported in 46 (79.3%) and an epidural blood patch was performed in 26 women (44.8%). Superior sagittal sinus, transverse sinus, and cortical veins were the most common sites of thrombosis. The median time to diagnosis was 6.5 days from delivery. Magnetic resonance imaging was the most common diagnostic neuro-imaging modality. Full neurological recovery was reported in 48 (82.8%), whilst neurological deficits were reported in six (10.3%) women. DISCUSSION: The diagnosis of CVST may be overlooked in women who present with headache following neuraxial block. A change in character of headache with loss of postural element, and focal neurological signs are the key clinical features that could help anaesthetists differentiate headache of CVST from PDPH. The high reported rates of ADP and PDPH lend support to their possible association with CVST.

Horner's syndrome following obstetric neuraxial blockade - a systematic review of the literature.

Horner's syndrome is a rarely reported complication of neuraxial blockade. In obstetric practice, the neurological signs of Horner's syndrome may cause anxiety amongst patients and healthcare staff, but more importantly may herald the onset of maternal hypotension. Medline, CINAHL, and EMBASE databases were searched to identify cases of Horner's syndrome following obstetric neuraxial blockade. Anaesthetic technique, clinical features, anaesthetic management of the Horner's syndrome and time to resolution were assessed. Seventy-eight case reports of Horner's syndrome following obstetric neuraxial blockade were identified. Nine cases also had trigeminal nerve palsy and one case had hypoglossal nerve palsy. Amongst the 78 cases, 74% developed Horner's syndrome within one hour of a local anaesthetic bolus. The median time for resolution of Horner's syndrome was two hours, though one case was permanent. One case of Horner's syndrome was found to be due to an internal carotid artery dissection. Some cases of Horner's syndrome resolved spontaneously despite ongoing administration of epidural local anaesthetic. Hypotension was reported in 13%. Horner's syndrome is usually a benign phenomenon, the consequence of high cephalad spread of local anaesthetic, that resolves spontaneously within a few hours. Patients with a persistent Horner's syndrome, or one associated with atypical features such as neck pain, should undergo a diagnostic workup including magnetic resonance angiography of the neck. The dermatomal level of neuraxial blockade, maternal and fetal well-being should be taken into account when making decisions regarding neuraxial blockade. The presence of Horner's syndrome alone should not lead to discontinuation of neuraxial blockade.

Cranial nerve palsy following central neuraxial block in obstetrics - a review of the literature and analysis of 43 case reports.

BACKGROUND: Cranial nerve palsy is a rarely reported complication of central neuraxial block in obstetrics. The aetiology is diverse and includes both decreased and increased intracranial pressure. METHODS: Medline, CINAHL, and EMBASE databases were searched to identify cases of cranial nerve palsy following obstetric central neuraxial block. Possible aetiology, clinical symptoms and signs, treatment, and time to resolution were assessed. RESULTS: Forty-one articles containing 43 case reports of cranial nerve palsy following obstetric central neuraxial block were identified. Four cranial nerve palsies were bilateral; the remainder being unilateral. The cranial nerves most commonly affected were the abducens (17 case reports) and facial (12 case reports) nerves. Epidural block was implicated in 25 cases. Classical post-dural puncture headache preceded cranial nerve palsy in 27 cases. Subdural haematomas were reported in six cases and cortical venous or transverse sinus thrombosis in one case. Epidural blood patch was administered for treatment of cranial nerve palsy in 17 cases. Thirty-five patients had complete resolution of symptoms but in eight the cranial nerve palsy was permanent. No case reports of olfactory, oculomotor, glossopharyngeal, accessory or hypoglossal nerve palsy were identified. CONCLUSION: Intracranial hypotension is the most common aetiology of cranial nerve palsy after central neuraxial block in obstetrics. Neuroimaging is recommended in every case, to exclude other neurological causes. Epidural blood patch was the most utilised treatment for post-dural puncture cranial nerve palsy, but outcomes were variable. The majority of cranial nerve palsies resolved over the subsequent weeks and months.

Free radicals and cardioplegia: organic anti-oxidants as additives to the St Thomas' Hospital cardioplegic solution.

The isolated perfused working rat heart model of cardiopulmonary bypass and ischaemic cardiac arrest has been used to investigate whether addition of various organic anti-oxidants to the St Thomas' Hospital cardioplegic solution can enhance the recovery of function of the rat myocardium after normothermic (37 degrees C) global ischaemic arrest. Five anti-oxidants were studied: (i) ascorbate (1.0 and 10.0 mmol.litre-1), (ii) methionine (1.0 and 10.0 mmol.litre-1), (iii) reduced glutathione (1.0 and 10.0 mmol.litre-1), (iv) dimethylthiourea (0.1, 1.0, 10.0 and 50.0 mmol.litre-1), (v) N-2-mercaptopropionyl glycine (0.1, 1.0 and 10.0 mmol.litre-1). The recovery of aortic flow in control hearts which were free of anti-oxidant was 50.7(SEM 0.5)%; ascorbate (1.0 or 10.0 mmol.litre-1) improved this recovery to 72.1(1.7) and 70.2(0.3)% respectively; methionine (1.0 and 10.0 mmol.litre-1) improved the recovery to 74.1(5.7)% and 67.7(1.7)%, respectively; reduced glutathione (1.0 and 10.0 mmol.litre-1) improved the recovery to 66.7(1.4)% and 74.0(1.7)% respectively. In further studies, the addition of dimethylthiourea (0.1, 1.0 and 10.0 mmol.litre-1) to the cardioplegic solution failed to improve recovery of aortic flow [47.3(8.0), 24.6(7.3), 48.0(7.7)% respectively] when compared to its anti-oxidant free control value of 40.4(6.1)% and at a concentration of 50.0 mmol.litre-1 a very poor recovery of aortic flow of 7.7(4.8)% was observed. Mercaptopropionyl glycine (0.1, 1.0 and 10.0 mmol.litre-1) also failed to improve the recovery of aortic flow [34.7(1.6), 34.7(7.7) and 25.6(5.4)% respectively.2+ Since biological membranes are highly permeable to dimethylthiourea and mercaptopropionyl glycine, it is possible that they accumulate in the intracellular compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental study of intermittent crossclamping with fibrillation and myocardial protection: reduced injury from shorter cumulative ischemia or intrinsic protective effect?

OBJECTIVE: During coronary artery revascularization, some surgeons favor intermittent crossclamping with ventricular fibrillation in preference to cardioplegic ischemic arrest for myocardial protection. It is unclear, however, whether intermittent crossclamping with fibrillation is equally protective or whether ischemic injury is reduced as a consequence of shorter cumulative ischemia. METHODS: We used isolated, Langendorff-perfused rat hearts, measured preischemic function (left ventricular developed pressure) with an intraventricular balloon, and then subjected the hearts to either (1) 40 minutes of global ischemia, (2) a 2-minute infusion of cardioplegic solution and 40 minutes of ischemia, (3) multidose (every 10 minutes) infusions of cardioplegic solution during 40 minutes of ischemia, (4) continuous ventricular fibrillation during 40 minutes of ischemia, (5) intermittent (4 x 10 minutes) ischemia with 10 minutes of reperfusion, (6) intermittent (4 x 10 minutes) ischemia preceded by intermittent cardioplegia, (7) intermittent (4 x 10 minutes) ischemia with ventricular fibrillation, (8) continuous (40 minutes) ventricular fibrillation during coronary perfusion, or (9) intermittent (4 x 10 minutes) ventricular fibrillation (with perfusion). All protocols were followed by 60 minutes of reperfusion. RESULTS: After 60 minutes of reperfusion, the percentage recovery of left ventricular developed pressure for groups 1 through 9 was as follows: 32% +/- 2%, 57% +/- 6%, 82% +/- 3%, 19% +/- 3%, 73% +/- 3%, 70% +/- 3%, 78% +/- 4%, 55% +/- 2%, and 57% +/- 3%, respectively. No significant differences were identified among groups 3, 5, and 7, but the percentage recovery of developed pressure in group 3 was significantly higher than that in group 6; the degree of recovery in groups 3 and 5 to 7 was significantly (P <.05) higher than in groups 1, 2, 4, 8, and 9. Early recovery was significantly (P <.05) more rapid in groups 3 and 5 to 9, reaching a plateau (of 55%-80%) by 10 minutes of reperfusion; in groups 1, 2, and 4, the recovery plateau occurred after 50 minutes. Left ventricular end-diastolic pressure was elevated in groups 1, 2, and 4 but was almost unchanged from baseline in the other groups. CONCLUSIONS: A similar level of myocardial protection was achieved with multidose (intermittent) cardioplegia or intermittent crossclamping (with or without fibrillation), indicating that intrinsic preservation by intermittent crossclamping with fibrillation does not exacerbate ischemic injury.

Myocardial protection: the efficacy of an ultra-short-acting beta-blocker, esmolol, as a cardioplegic agent.

OBJECTIVE: During myocardial revascularization, some surgeons (particularly in the United Kingdom) use intermittent crossclamping with fibrillation as an alternative to cardioplegia. We recently showed that intermittent crossclamping with fibrillation has an intrinsic protection equivalent to that of cardioplegia. In this study we hypothesized that arrest, rather than fibrillation, during intermittent crossclamping may be beneficial. Because esmolol, an ultra-short-acting beta-blocker, is known to attenuate myocardial ischemia-reperfusion injury, we compared the protective effect of esmolol arrest with that of intermittent crossclamping with fibrillation and conventional cardioplegia (St Thomas' Hospital solution). METHODS: Isolated rat hearts were Langendorff perfused at either constant flow (14 mL/min) or constant pressure (75 mm Hg) with oxygenated Krebs-Henseleit bicarbonate buffer (37 degrees C), and left ventricular developed pressure was assessed. In study 1 (constant flow perfusion) 8 groups (n = 6 hearts per group) were studied: (1) 40 minutes of global ischemia; (2) 2 minutes of St Thomas' Hospital infusion and 40 minutes of ischemia; (3) multidose (every 10 minutes) infusions of St Thomas' Hospital solution during 40 minutes of ischemia; (4) 2 minutes of esmolol infusion and 40 minutes of ischemia; (5) multidose (every 10 minutes) esmolol infusions during 40 minutes of ischemia; (6) continuous infusion of esmolol for 40 minutes during coronary perfusion; (7) intermittent (4 x 10 minutes) ischemia with ventricular fibrillation; and (8) intermittent (4 x 10 minutes) ischemia preceded by intermittent esmolol administration. All protocols were followed by 60 minutes of reperfusion. Further experiments (study 2) examined the esmolol administration method in hearts perfused by constant pressure. RESULTS: An optimal arresting dose of 1.0 mmol/L esmolol was established. In study 1 recovery of left ventricular developed pressure (expressed as percentage of preischemic value) was 7% +/- 4%, 28% +/- 8%, 70% +/- 5%, 8% +/- 1%, 90% +/- 4%, 65% +/- 3%, 71% +/- 5%, and 76% +/- 5% in groups 1 to 8, respectively. Intermittent esmolol arrest with global ischemia provided equivalent myocardial protection to intermittent crossclamping with fibrillation, continuous esmolol perfusion, and multidose St Thomas' Hospital solution. Surprisingly, multidose esmolol infusion was more protective than all other treatments. In further experiments (study 2) optimal recovery was obtained with multiple esmolol infusions (by constant flow or constant pressure), but continuous esmolol infusion (at constant flow) was less effective than constant pressure infusion. CONCLUSIONS: Intermittent arrest with esmolol did not enhance protection of intermittent crossclamping with fibrillation; however, multiple esmolol infusions during global ischemia provided improved protection. Administration (constant flow or constant pressure) of arresting solutions influenced outcome only during continuous infusion. Multidose esmolol arrest may be a beneficial alternative to intermittent crossclamping with fibrillation or conventional cardioplegia.

Effect of sodium aspartate on the recovery of the rat heart from long-term hypothermic storage.

We have investigated the reported ability of aspartate to enhance greatly the cardioprotective properties of the St. Thomas' Hospital cardioplegic solution after prolonged hypothermic storage. Rat hearts (n = 8 per group) were excised and subjected to immediate arrest with St. Thomas' Hospital cardioplegic solution (2 minutes at 4 degrees C) with or without addition of monosodium aspartate (20 mmol/L). The hearts were then immersed in the same solution for 8 hours (4 degrees C) before heterotopic transplantation into the abdomen of homozygous rats and reperfusion in vivo for 24 hours. The hearts were then excised and perfused in the Langendorff mode (20 minutes). Addition of aspartate to St. Thomas' Hospital cardioplegic solution gave a small but significant improvement in left ventricular developed pressure, which recovered to 82 +/- 3 mm Hg compared with 70 +/- 2 mm Hg in control hearts (p less than 0.05). However, coronary flow and high-energy phosphate content were similar in both groups. In subsequent experiments hearts (n = 8 per group) were excised, arrested (2 minutes at 4 degrees C) with St. Thomas' Hospital cardioplegic solution containing a 0, 5, 10, 20, 30, 40, or 50 mmol/L concentration of aspartate, stored for 8 hours at 4 degrees C, and then reperfused for 35 minutes. A bell-shaped dose-response curve was obtained, with maximum recovery in the 20 mmol/L aspartate group (cardiac output, 48 +/- 5 ml/min versus 32 +/- 5 ml/min in the aspartate-free control group; p less than 0.05). However, additional experiments showed that a comparable improvement could be achieved simply by increasing the sodium concentration of St. Thomas' Hospital cardioplegic solution by 20 mmol/L. Similarly, if sodium aspartate (20 mmol/L) was added and the sodium content of the St. Thomas' Hospital cardioplegic solution reduced by 20 mmol/L, no significant protection was observed when recovery was compared with that of unmodified St. Thomas' Hospital cardioplegic solution alone. In still further studies, hearts (n = 8 per group) were perfused in the working mode at either high (greater than 80 ml/min) or low (less than 50 ml/min) left atrial filling rates. Under these conditions, if functional recovery was expressed as a percentage of preischemic function, artifactually high recoveries could be obtained in the low-filling-rate group. In conclusion, assessment of the protective properties of organic additives to cardioplegic solutions requires careful consideration of (1) the consequences of coincident changes in ionic composition and (2) the characteristics of the model used for assessment.

Long-term preservation of the mammalian myocardium. Effect of storage medium and temperature on the vulnerability to tissue injury.

Human heart preservation for transplantation commonly involves infusion of cold cardioplegic solutions and subsequent immersion in the same solution. The objectives of the present study were (1) to establish the temporal relationship between storage time (at 10 degrees C) and the postischemic recovery of function in the isolated rat heart, (2) to assess, by metabolic and functional measurements, whether storing the heart in fluid as opposed to moist air had any effect on the viability of the preparation, and (3) to ascertain the optimal storage temperature. Isolated rat hearts (at least 6 in each group) were infused for 3 minutes with St. Thomas' Hospital cardioplegic solution No. 2 at 10 degrees C, stored at 10 degrees C for 6, 12, 18, or 24 hours, and then reperfused at 37 degrees C. Mechanical function, assessed by construction of pressure-volume curves (balloon volumes: 20, 40, 60, 80, 100, and 120 microliters), was measured before ischemia and storage and after 60 minutes of reperfusion. Function deteriorated in a time-dependent manner; thus at a balloon volume of 60 microliters the recovery of left ventricular developed pressure was 84.2% +/- 5.3% after 6 hours (p = not significant when compared with preischemic control); 69.1 +/- 3.3% after 12 hours (p less than 0.05); 55.6% +/- 4.4% after 18 hours (p less than 0.05), and 53.0% +/- 6.8% (p less than 0.05) after 24 hours of storage. Other indices of cardiac function, together with creatine kinase leakage and high-energy phosphate content, supported these observations. Since the recovery of the left ventricular developed pressure balloon volume curves were essentially flat after 18 and 24 hours of storage, either 6 or 12 hours of storage were therefore used in subsequent studies. Comparison of storage environment (hearts either immersed in St. Thomas Hospital cardioplegic solution No. 2 or suspended in moist air at 10 degrees C for 6 or 12 hours) revealed no significant differences in functional recovery between the groups. Thus hearts recovered 94.9% +/- 3.5% and 113.7% +/- 12.4%, respectively, after 6 hours of storage and 71.6% +/- 2.4% and 54.2% +/- 7.9%, respectively, after 12 hours of storage. Enzyme leakage and tissue water gain were also similar in both groups of hearts. Finally, hearts (n = 6 per group) were subjected to 12 hours' storage at 1.0 degree, 5.0 degrees, 7.5 degrees, 10.0 degrees, 12.5 degrees, 15.0 degrees, and 20.0 degrees C.(ABSTRACT TRUNCATED AT 400 WORDS)

Optimal myocardial protection during crystalloid cardioplegia. Interrelationship between volume and duration of infusion.

There is often a large difference between volumes of crystalloid cardioplegic solution used clinically (2 to 4 ml/gm myocardium) and experimentally (in rat heart preparations, volumes of 30 ml/gm or more are used). In an attempt to reconcile these differences and define the minimum volume and/or duration of infusion of the St. Thomas' Hospital cardioplegic solution consistent with maximal myocardial protection, we have used the isolated working rat heart to characterize the relationships between myocardial protection and (1) the duration of cardioplegic infusion and (2) the volume of cardioplegic infusion. Hearts (n = 6 per group, weighing 0.90 +/- 0.06 gm) were subjected to 0, 5, 10, 15, 30, 45, 60, 120, 180, 240, or 300 seconds of cardioplegic infusion (mean infusion volumes = 0, 1.3 +/- 0.1, 2.0 +/- 0.1, 2.8 +/- 0.2, 5.0 +/- 0.1, 8.3 +/- 0.2, 10.5 +/- 0.8, 21.8 +/- 2.1, 22.7 +/- 1.3, 32.3 +/- 2.1, and 39.1 +/- 1.8 ml per heart, respectively) before 30 minutes of normothermic ischemia. They recovered 3.9% +/- 2.3%, 9.7% +/- 5.0%, 22.8% +/- 5.8%, 34.6% +/- 4.6%, 54.7% +/- 6.6%, 64.0% +/- 5.0%, 67.4% +/- 4.0%, 56.6% +/- 11.1%, 60.0% +/- 5.8%, 51.6% +/- 7.0%, and 68.0% +/- 7.8% of their preischemic cardiac output on reperfusion. Creatine kinase leakage, tissue adenosine triphosphate and creatine phosphate content, and other indices of cardiac function supported this observation. To assess volume of infusion rather than duration, we infused hearts (n = 6 per group) with 1.0, 1.5, or 2.0 ml of cardioplegic solution over 120 seconds. Although recovery of cardiac output with 2.0 ml (56.2% +/- 6.8%) was not significantly different from that (56.6% +/- 11.1%) observed with large volumes of solution (21.9 +/- 2.1 ml), infusion of 1.5 and 1.0 ml resulted in poor recovery of cardiac output (40.1% +/- 4.6% and 21.8% +/- 3.9%, respectively). To assess duration (with low volumes) rather than volume of infusion, we infused hearts (n = 6 per group) with 2.0 ml of cardioplegic solution over 10, 30, 60, or 120 seconds. Maximal protection was observed with 30, 60, and 120 seconds of infusion (recovery of cardiac output = 56.7% +/- 5.9%, 45.1% +/- 7.9%, and 56.2% +/- 6.8%, respectively). Our results suggest that, for maximum myocardial protection, the St. Thomas' Hospital solution should be infused at a rate of not less than 2.0 ml/gm wet weight of heart and that the duration of infusion should be not less than 30 seconds.

Long-term myocardial preservation: effects of hyperkalemia, sodium channel, and Na/K/2Cl cotransport inhibition on extracellular potassium accumulation during hypothermic storage.

OBJECTIVES: We previously demonstrated improved myocardial preservation with polarized (tetrodotoxin-induced), compared with depolarized (hyperkalemia-induced), arrest and hypothermic storage. This study was undertaken to determine whether polarized arrest reduced ionic imbalance during ischemic storage and whether this was influenced by Na+/K +/2Cl- cotransport inhibition. METHODS: We used the isolated crystalloid perfused working rat heart preparation (1) to measure extracellular K+ accumulation (using a K+-sensitive intramyocardial electrode) during ischemic (control), depolarized (K+ 16 mmol/L), and polarized (tetrodotoxin, 22 micromol/L) arrest and hypothermic (7.5 degrees C) storage (5 hours), (2) to determine dose-dependent (0.1, 1.0, 10 and 100 micromol/L) effects of the Na +/K+/2Cl- cotransport inhibitor, furosemide, on extracellular K+ accumulation during polarized arrest and 7.5 degrees C storage, and (3) to correlate extracellular K+ accumulation to postischemic recovery of cardiac function. RESULTS: Characteristic triphasic profiles of extracellular K+ accumulation were observed in control and depolarized arrested hearts; a significantly attenuated profile with polarized arrested hearts demonstrated reduced extracellular K+ accumulation, correlating with higher postischemic function (recovery of aortic flow was 54% +/-4% [P =.01] compared with 39% +/-3% and 32% +/-3% in depolarized and control hearts, respectively). Furosemide (0.1, 1.0, 10, and 100 micromol/L) modified extracellular K+ accumulation by -18%, -38%, -0.2%, and +9%, respectively, after 30 minutes and by -4%, -27%, +31%, and +42%, respectively, after 5 hours of polarized storage. Recovery of aortic flow was 53% +/-4% (polarized arrest alone), 56% +/-8%, 70% +/-2% (P =.04 vs control), 69% +/-4% (P =.04 vs control), and 65% +/-3% ( P =. 04 vs control), respectively. CONCLUSIONS: Polarized arrest was associated with a reduced ionic imbalance (demonstrated by reduced extracellular K+ accumulation) and improved recovery of cardiac function. Further attenuation of extracellular K + accumulation (by furosemide) resulted in additional recovery.

Harvesting hearts for long-term preservation. Detrimental effects of initial hypothermic infusion of cardioplegic solutions.

Current procedure for harvesting human donor hearts for long-term storage before transplantation involves direct infusion of a hypothermic (4 degrees C) crystalloid cardioplegic solution into the normothermic (37 degrees C) heart in situ. We used the isolated perfused working rat heart preparation to investigate whether infusing cold crystalloid solutions into normothermic blood-containing hearts was consistent with maximal myocardial protection. Hearts (n = 6 per group) were excised and subjected to a primary (1 minute) infusion with either the St. Thomas' Hospital cardioplegic solution or a bicarbonate buffer solution, at 7.5 degrees C, 22 degrees C, or 37 degrees C. This was followed by a secondary infusion (2 minutes) with cold (7.5 degrees C) cardioplegic solution, after which all hearts were stored at 7.5 degrees C for 6 hours and then reperfused at 37 degrees C for 60 minutes, during which time creatine kinase leakage and cardiac function were measured. Primary infusion with warm solutions resulted in (1) decreased coronary vascular resistance during cardioplegic infusion and (2) greater postischemic cardiac function. This suggests that their use, before the standard cold infusion, might be beneficial to the long-term preservation of transplant donor hearts.

Transient hypocalcemic reperfusion does not improve postischemic recovery in the rat heart after preservation with St. Thomas' Hospital cardioplegic solution.

We used the isolated perfused working rat heart to investigate the effects of transient hypocalcemic reperfusion after cardioplegic arrest with the St. Thomas' Hospital cardioplegic solution and 25 minutes of global normothermic (37 degrees C) ischemia. Hearts were reperfused (Langendorff mode) transiently (20 minutes) with solutions containing various concentrations of calcium; this was followed by 30 minutes of reperfusion with standard (1.4 mmol/L, the physiologic concentration) calcium buffer (10 minutes in the Langendorff mode and 20 minutes in the working mode). Recovery of cardiac output in control hearts (calcium concentration 1.4 mmol/L throughout) was 51.7% +/- 4.6%; in hearts transiently reperfused with hypocalcemic buffer (0.25, 0.5, 0.75, or 1.0 mmol/L) the recoveries of cardiac output were 49.3% +/- 6.4%, 52.2% +/- 7.2%, 58.7% +/- 3.2%, and 47.2 +/- 4.7%, respectively (all not significant), whereas recovery was only 14.7% +/- 2.8% (p less than 0.05) in hearts transiently reperfused with calcium 0.1 mmol/L. Creatine kinase leakage was significantly (p less than 0.05) greater in the group reperfused with calcium 0.1 mmol/L, but it did not vary significantly between the other groups. Tissue high-energy phosphate content was similar and in the normal range in all groups except for the group reperfused with calcium 0.1 mmol/L. In further experiments, the duration of hypocalcemic (0.5 mmol/L) reperfusion was varied (0, 5, 10, 15, 20, or 30 minutes). No significant differences in recovery of cardiac output were observed (58.2% +/- 5.0%, 52.3% +/- 5.7%, 52.0% +/- 8.2%, 61.2% +/- 5.0%, 62.2% +/- 4.3%, and 66.2% +/- 3.2%, respectively). In additional studies, the standard calcium concentration (1.4 mmol/L) used before and after ischemia was replaced by hypercalcemic solution (2.5 mmol/L). Despite this, transient (10 minutes) hypocalcemic (0.5 mmol/L) reperfusion did not improve recovery. Finally, studies were undertaken with a longer duration of ischemia (40 minutes), and although recovery of cardiac output in the hypocalcemic group (0.5 mmol/L for 10 minutes) tended to be higher than in the control group (29.7% +/- 4.8% versus 18.5% +/- 4.9%, respectively), statistical significance was not achieved. We conclude that in these studies transient hypocalcemic reperfusion did not afford any additional protection over and above that afforded by cardioplegia alone.

Alpha-stat acid-base regulation during cardiopulmonary bypass improves neuropsychologic outcome in patients undergoing coronary artery bypass grafting.

Neuropsychologic impairment in patients undergoing cardiopulmonary bypass may be associated with cerebral blood flow changes arising from different management protocols for carbon dioxide tension during bypass. Seventy patients having coronary artery bypass grafting were randomized to either pH-stat or alpha-stat acid-base management during cardiopulmonary bypass with a membrane oxygenator. In each patient, cerebral blood flow (xenon 133 clearance), middle cerebral artery blood flow velocity (transcranial Doppler sonography), and cerebral oxygen metabolism (cerebral metabolic rate and cerebral extraction ratio) were measured during four phases of the operation: before bypass, during bypass (at hypothermia and at normothermia), and after bypass. A battery, of neuropsychologic tests were also conducted before and 6 weeks after the operation. During hypothermic (28 degrees C) bypass, cerebral blood flow was significantly (p < 0.001) greater in the pH-stat group (41 mlx100 gm(-1)xmin(-1); 95% confidence interval 39 to 43 mlx100 gm(-1)xmin(-1)) than in the alpha-stat group (24 mlx100 gm(-1)xmin(-1); confidence interval 22 to 26 mlx100 gm(-1)xmin(-1)) at constant pressure and How. Arterial carbon dioxide tensions were 41 mm Hg (40 to 41 mm Hg) and 26 mm Hg (25 to 27 mm Hg), respectively; pH was 7.36 (7.34 to 7.38) and 7.53 (7.51 to 7.55), respectively. Middle cerebral artery flow velocity was significantly (p < 0.05) reduced in the alpha-stat group to 87% (77% to 96%) of the prebypass value, whereas it was significantly (p < 0.05) increased (152%; 141% to 162%) in the pH-stat group. Cerebral extraction ratio for oxygen demonstrated relative cerebral hyperemia during hypothermic (28 degrees C) bypass in both the pH-stat and alpha-stat groups (0.12 [0.11 to 0.14] and 0.25 [0.22 to 0.28], respectively); however, hyperemia was significantly more pronounced in the pH-stat group, indicating greater disruption in cerebral autoregulation. Neuropsychologic impairment criteria of deterioration in results of three or more tests revealed that a significantly (Fisher's exact test, p = 0.02) higher proportion of patients in the pH-stat group fared poorly than in the alpha-stat group at 6 weeks (17/35, 48.6% [32% to 65.1%], and 7/35, 20% [6.7% to 33.2.2%], respectively). In conclusion, patients receiving alpha-stat management had less disruption of cerebral autoregulation during cardiopulmonary bypass, accompanied by a reduced incidence of postoperative cerebral dysfunction.

Long-term preservation of the heart: the effect of infusion pressure during continuous hypothermic cardioplegia.

Continuous hypothermic low-flow infusion of cardioplegic or other preservation solutions has been advocated for extending the maximum duration of storage of donor hearts for transplantation. We report the effect of varying the pressure during continuous infusion of St. Thomas' Hospital cardioplegic solution on functional recovery after long-term storage. Isolated working rat hearts (six per group) were aerobically perfused (20 minutes), and control indexes of cardiac function were measured; hypothermic ischemic arrest was then induced by a 3-minute infusion (60 cm H2O) of cold (7.5 degrees C) St. Thomas' Hospital cardioplegic solution. Hearts were then stored for 8 hours at 7.5 degrees C, either immersed in St. Thomas' Hospital cardioplegic solution (noninfused control) or continuously infused at varying infusion pressures with St. Thomas' Hospital cardioplegic solution, which had been both oxygenated and supplemented by the addition of glucose (11.1 mmol/L). After 8 hours of hypothermic ischemia, the rate of cardioplegic infusion was measured as an index of vascular resistance. The hearts were then reperfused (Langendorff) for 30 minutes during which creatine kinase leakage was measured. The hearts were then converted to working preparations for 20 minutes, and the recovery of contractile function was measured and expressed as a percentage of the preischemic control value. In hearts that had been subjected to continuous infusion at 6, 10, 20, 30, 40, and 60 cm H2O, the recoveries of aortic flow were 0% (p less than 0.05), 38.6% +/- 5.1% (p less than 0.05), 36.2% +/- 3.6% (p less than 0.05), 14.0% +/- 8.0%, 5.8% +/- 2.9%, and 9.9% +/- 4.7%, respectively, and the postischemic leakage of creatine kinase was 98.7 +/- 19.5 (p less than 0.05), 26.2 +/- 4.2, 15.5 +/- 3.4, 30.4 +/- 11.1, 109.8 +/- 21.8 (p less than 0.05), and 136.0 +/- 14.1 (p less than 0.05) IU/30 min/gm dry weight, respectively. In contrast, in noninfused control hearts the recovery of aortic flow was 11.1% +/- 7.5%, and creatine kinase leakage was 58.9 +/- 8.7 IU/30 min/gm dry weight. In conclusion, maximum myocardial preservation was obtained with continuous low-flow hypothermic cardioplegic infusion at pressures between 10 and 20 cm H2O.

Developments in cardioprotection: "polarized" arrest as an alternative to "depolarized" arrest.

During cardiac surgery or cardiac transplantation, the heart is subjected to varying periods of global ischemia. The heart must be protected during this ischemic period to avoid additional injury, and techniques have been developed that delay ischemic injury and minimize reperfusion injury. Almost universally, this involves using a hyperkalemic cardioplegic solution and these solutions have become the gold standard for myocardial protection for more than 20 years. Despite the extensive and continued research aimed at improving these basic hyperkalemic cardioplegic solutions, patients undergoing surgery almost invariably experience some degree of postoperative dysfunction. It is likely that this relates to the depolarizing nature of hyperkalemic solutions, which results in ionic imbalance caused by continuing transmembrane fluxes and the consequent maintenance of high energy phosphate metabolism, even during hypothermic ischemia. A potentially beneficial alternative to hyperkalemic cardioplegia is to arrest the heart in a "hyperpolarized" or "polarized" state, which maintains the membrane potential of the arrested myocardium at or near to the resting membrane potential. At these potentials, transmembrane fluxes will be minimized and there should be little metabolic demand, resulting in improved myocardial protection. Recent studies have explored these alternative concepts for myocardial protection. The use of compounds such as adenosine or potassium channel openers, which are thought to induce hyperpolarized arrest, have demonstrated improved protection after normothermic, or short periods of hypothermic, ischemia when compared to hyperkalemic (depolarized) arrest. Similarly, studies from our own laboratory, in which the sodium channel blocker, tetrodotoxin, was used to induce polarized arrest (demonstrated by direct measurement of membrane potential during ischemia) was also shown to provide better recovery of function after 5 hours of long-term hypothermic (7.5 degrees C) storage. These promising initial studies need to be consolidated before experimental promise becomes clinical reality.

Free radicals and cardioplegia: allopurinol and oxypurinol reduce myocardial injury following ischemic arrest.

Oxygen-derived free radicals generated by xanthine oxidase may represent a major cause of myocardial injury during ischemia and reperfusion. We have used the isolated working rat heart model of cardiopulmonary bypass and ischemic arrest to assess whether allopurinol or oxypurinol, which should prevent free radical formation through their ability to inhibit xanthine oxidase, can improve postischemic myocardial recovery when the drugs are administered either chronically (pretreatment) or acutely (as an addition to the cardioplegic or reperfusion solution). With normothermic ischemic arrest, both drugs, when given either chronically or acutely, significantly improved postischemic recovery of function. However, under hypothermic conditions, allopurinol conferred no protection when given either as pretreatment or during reperfusion, but it was effective when added to the cardioplegic solution. When administered under the appropriate conditions, both allopurinol and oxypurinol enhanced the protective effect afforded by the St. Thomas' Hospital cardioplegic solution, possibly by inhibiting xanthine oxidase activity and preventing the formation of oxygen-derived free radicals.

Cardiopulmonary bypass: perioperative cerebral blood flow and postoperative cognitive deficit.

Increased cerebral blood flow occurring during cardiopulmonary bypass as a result of changes in arterial carbon dioxide tension during acid-base regulation is thought to increase postoperative cognitive dysfunction. We studied 70 patients undergoing coronary artery bypass procedures who were randomized to two different acid-base protocols: pH-stat or alpha-stat regulation. Cerebral blood flow, cerebral blood flow velocity, and cerebral oxygen metabolism were measured before bypass, during bypass (hypothermic [28 degrees C] and normothermic phases), and after bypass. Detailed cognitive tests were conducted before operation and 6 weeks after operation. During 28 degrees C bypass, cerebral blood flow was significantly (p < 0.05) higher in the pH-stat group than in the alpha-stat group (41 +/- 2 versus 24 +/- 2 mL.100 g-1.min-1), and cerebral blood flow velocity was significantly increased in the pH-stat group and significantly decreased in the alpha-stat group (152% +/- 10% versus 78% +/- 7%). Cerebral extraction ratio of oxygen demonstrated a relatively greater disruption of autoregulation in the pH-stat group than in the alpha-stat group with relative hyperemia of 0.12 +/- 0.02 versus 0.26 +/- 0.03, respectively, during 28 degrees C bypass. Using the criterion of deterioration in three or more neuropsychologic tests, a significantly higher proportion of patients in the pH-stat group fared less well than in the alpha-stat group (49% +/- 17% versus 20% +/- 13%). Patients in the alpha-stat group experienced less disruption of cerebral autoregulation during hypothermic cardiopulmonary bypass, and this was accompanied by a reduction in postoperative cognitive dysfunction.

Ischemic preconditioning enhances recovery of isolated rat lungs after hypothermic preservation.

BACKGROUND: Ischemic preconditioning, an endogenous protection mechanism, occurs in many organs, including lungs. The efficacies of differing ischemic durations in protecting the lung are unknown. We compared the ability of three preconditioning protocols to protect rat lungs during storage. METHODS: Function was measured in five groups of perfused, ventilated rat lungs. Group 1 lungs underwent control perfusion (60 minutes) without storage. Groups 2 through 5 underwent the following prestorage protocols: group 2, 20 minutes of perfusion; group 3, 10 minutes of perfusion, 5 minutes of cessation of ventilation and perfusion (ischemia), and 5 minutes of reperfusion; group 4, 5 minutes of perfusion, 10 minutes of ischemia, and 5 minutes of reperfusion; and group 5, 2 periods of 5 minutes of ischemia and 5 minutes of reperfusion. Lungs were then flushed with, and immersed (6 hours) in modified bicarbonate buffer (4 degrees C). Lung function was reassessed during 40 minutes of reperfusion (37 degrees C). Subsequently we examined preconditioning by stopping ventilation or perfusion separately. RESULTS: After reperfusion, lungs in group 2 had a compliance of 0.015+/-0.002 mL/cm H2O (mean +/- SE, n = 10), significantly lower than lungs in group 1 (0.063+/-0.002 mL/cm H2O). Ischemic preconditioning was protective, with lungs in groups 3, 4, and 5 having compliances greater (p<0.05) than those in group 2. Preconditioning by cessation of ventilation alone was also effective. CONCLUSIONS: Preconditioning attenuates deterioration in lung compliance on reperfusion to a degree dependent on the protocol used.

Theophylline improves functional recovery of isolated rat lungs after hypothermic preservation.

BACKGROUND: Raising intracellular cyclic adenosine monophosphate levels protects lungs from ischemia-reperfusion injury. We hypothesized that the phosphodiesterase inhibitor theophylline would protect lungs during storage. METHODS: Rat lungs were perfused with modified bicarbonate buffer mixed with rat blood (4:1 vol/vol) (37 degrees C) and ventilated (80 breaths/min). After 20 minutes of perfusion during which vascular resistance and airway compliance were measured, lungs were flushed with and then immersed in bicarbonate buffer (4 degrees C) alone or containing theophylline (30 to 1,000 micromol/L). After 6 hours of storage, lung function was reassessed during 40 minutes of reperfusion. RESULTS: Lungs stored in the presence of theophylline had improved lung function on reperfusion. After 40 minutes of reperfusion, pulmonary compliance was 0.008+/-0.004 mL/cm H2O, 0.022+/-0.010, 0.037+/-0.007, 0.044+/-0.006, and 0.073+/-0.003 mL/cm H2O, and vascular resistance was 3.84+/-0.40 cm H2O x min x mL(-1), 3.64+/-0.78, 2.12+/-0.35, 2.22+/-0.25, and 1.90+/-0.38 cm H2O x min x mL(-1) in lungs stored in the presence of 0, 30, 100, 300, or 1,000 micromol/L theophylline, respectively. Similar improvements were obtained for wet to dry weight ratio and gas exchange. CONCLUSIONS: Theophylline merits investigation as a potentially beneficial addition to solutions for the flushing and storage of human lungs for transplantation.