Lars-Erik Linder

Long-term intrathecal morphine and bupivacaine in “refractory” cancer pain. I. Results from the first series of 52 patients

Neither epidural (EDA) or intrathecal (IT) morphine nor EDA opiate + bupivacaine provides acceptable relief of some types of cancer pain, e. g. pain originating from mucocutaneous ulcers, deafferentation pain, continuous and intermittent visceral and ischaemic pain, and that occurring with body movement as a result of a fracture. To improve pain relief in such conditions, we gave combinations of morphine and bupivacaine through open IT‐catheters to 52 patients with “refractory”, severe (VAS 7–10 out of 10), complex cancer pain (Edmonton Stage‐3), for periods of 1–305 (median = 23) days. The efficacy of the treatment was estimated from: 1) daily dosage (intraspinal and total opiates, and intraspinal bupivacaine), and 2) scores of non‐opiate analgesic and sedative consumption, gait and daily activities, and amount and pattern of sleep. Forty‐four patients obtained continuous and acceptable pain relief (VAS 0–2), 26 of them with daily doses of IT‐bupivacaine of <30 mg/day (<1. 5 mg/h). Higher IT‐bupivacaine doses (>60–305 mg/day), not always giving acceptable pain relief, were necessary in 13 patients with deafferentation pain from the spinal cord or brachial or lumbosacral plexuses or pain from the coeliac plexus, or from large, ulcerated mucocutaneous tumours. By combining IT‐bupivacaine with IT‐morphine, it was possible to use relatively low IT‐morphine doses (10–25 mg/day during the first 2 months of treatment) in more than half of the patients. The IT‐treatment significantly decreased the total (all routes) opiate consumption and significandy improved sleep, gait and daily activities. For the whole period of observation (6 months), the IT‐treatment was assessed as adequate in 3. 8%, good in 23. 1%, very good in 59. 6% and excellent in 13. 5% of the cases. Adverse effects of the IT‐bupivacaine (paraesthesiae, paresis, gait impairment, urinary retention, anal sphincter disturbances and orthostatic hypotension) did not occur with doses of 2. 5–3. 0 mg/h (approx. 60–70 mg/day).

Epidural versus intrathecal morphine-bupivacaine: Assessment of consecutive treatments in advanced cancer pain

Twenty-five patients with multifocal and multitype (somatic, visceral, and neurogenic) advanced cancer pain who experienced severe pain despite extradural (ED) morphine and bupivacaine were converted to intrathecal (IT) morphine and bupivacaine. The consecutive ED and IT periods (2-174 days, median = 50 days, and 1-305 days, median = 37 days, respectively) were assessed in clinical terms (daily analgesic dosages giving acceptable pain relief and quality of life expressed as sleeping hours and walking/daily activities). With the IT treatment, the total (all routes) opiate consumption and the daily doses of spinal morphine and spinal bupivacaine decreased significantly at the beginning of the treatment compared to the ED period, and continued to be significantly reduced for up to 1 wk for spinal opiate and bupivacaine and 6 mo for total opiate. The spinal opiate and bupivacaine doses were still lower in 50% of the patients at the end of the IT treatment compared to the end of the ED period. When final ED versus initial (2nd day) IT doses were assessed, the daily median dose ratios were 7.5 for total opiate and 4 for both spinal opiate and bupivacaine. Subsequently, lower daily volumes and higher concentrations were needed for IT administration of the drugs. During the first month of the IT treatment, sleeping and walking scores improved compared to ED treatment. Thus, the IT treatment gave more satisfactory pain relief, and--because of lower daily doses and volume--proved to be more suitable for treatment at home (continuous infusion from external pumps) than the ED treatment.

Stiffness of Central Venous Catheters

Catheter stiffness has been suggested to be a principal factor in the thrombogenesis encountered after central venous cannulation. However, no data have been published to date about the stiffness of central venous catheters. A method for measuring catheter stiffness has been developed. The force needed to deflect a catheter tip 1.2 mm from a fastening point was measured with the help of a cantilever beam (Grass Model DA‐7). Six different sections of each catheter were measured, and the final results expressed as an average of these. Twenty‐seven central venous catheters made of silicone elastomer, polyurethane, polyvinylchloride, polyethylene and teflon were tested. The bending stiffness, EI (E=elastic modulus of the material, I = moment of inertia of catheter (a geometrical property)) was below 16×10‐6 Nm2 for all catheters made of silicone elastomer, polyvinylchloride and polyurethane. Polyethylene catheters were stiffer, but could be made softer by reduction of their diameters. Teflon catheters were up to 10 times stiffer than the catheters in the soft group. Heparinization and radioopacity of catheters do not significantly alter their bending stiffness. In a concomitant study the results indicate that there is a significantly lower incidence of thrombus formation in catheters with a bending stiffness below 16×10‐6 Nm2.

Material Thrombogenicity in Central Venous Catheterization I. A Comparison Between Uncoated and Heparin‐Coated, Long Antebrachial, Polyethylene Catheters

In order to evaluate a new method of heparinization, uncoated (22) and heparin‐coated (27) central venous polyethylene catheters were inserted in 49 patients via basilic and cephalic veins punctured at the fossa cubiti. The mean duration of catheterization was 5.7 (1–11) days. One‐third of the patients with heparin‐coated catheters, and one sixth with uncoated catheters developed clinical thrombophlebitis, with a maximum incidence between 4 and 8 days after catheterization. A higher risk of developing thrombophlebitia in the first 4 days after catheterization was found in the patients with heparin‐coated polyethylene catheters. After 8 days of catheterization, it seems that there is a lower risk of new cases of thrombophlebitis appearing both in patients with uncoated and those with heparin‐coated polyethylene catheters. Radiological thrombosis, regardless of duration of catheterization and heparin‐coating, was demonstrated in all 22 patients investigated by “pull‐out” phlebography. The heparin‐coating did not decrease the rate of thrombotic complications. Location of the catheter tip in subclavian veins was associated with a significantly higher incidence of large, parietal thrombi and catheter occlusion than when the tip was situated in anonymous veins, the superior vena cava, or the right atrium. Cannulation by heparin‐coated, polyethylene tubing did not reduce the rate of catheter occlusion.

Reversibility of the blood‐brain barrier dysfunction induced by acute hypertension

An acute hypertensive episode of short duration (<3 mm) induced by i.v. injection of angiotensin in rats resulted in a blood‐brain barrier dysfunction that was rapidly reversible. Thus, no macroscopic extravasation was seen when Evans blue was given 10 or 20 min after angiotensin. A faint fluorescence (Evans blue‐albumin) was seen in the walls of some intracerebral arterioles in a few rats given the tracer 10 min after angiotensin.

BLOOD‐BRAIN BARRIER DYSFUNCTION IN ACUTE ARTERIAL HYPERTENSION INDUCED BY CLAMPING OF THE THORACIC AORTA

Acute experimental hypertension induced by clamping of the thoracic aorta resulted in blood‐brain barrier dysfunction as revealed by extravasation of Evans blue‐albumin in 10 out of 13 dogs. The tracer distribution was similar to that found in animals with metaraminol‐induced hypertension, which supports the hypothesis that the high intravascular pressure per se and not any toxic drug effect is the factor that brings about increased permeability to protein tracers.

Displacement of catheters inserted through internal jugular veins with neck flexion and extension. A preliminary study.

Displacement of central venous catheters inserted through internal jugular veins in adult man was estimated on chest x-rays in six patients and measured in six corpses. The downward displacement of the catheter tips with maximum neck flexion varied between 1.0 and 2.0 cm in patients, and between 1.0 and 2.5 cm in corpses. The upward displacement with maximum neck extension varied between 0.5 to 1.0 cm in patients and 0.5 to 1.5 cm in corpses. The total displacement varied between 1.5 to 3.0 cm in patients, and 1.5 to 4.0 cm in corpses. The geater displacement in corpses might be explained by detachment of sternocleidomastoid muscles, and by resection of the sternum and anterior ribs, performed for access to the heart and superior vena cava. There was no apparent correlation between the side and site of the vein puncture, body length, sternocleidomastoid length, distances from the punction sites to suprasternal notch, and values of the displacements of the catheter tips in any group. To avoid rhythm disturbances and perforation of the heart (possible complications of the catheter displacement), the necessity of locating central venous catheter tips 3.0 to 4.0 cm above the superior vena cava-right atrial junction, and firm fixation of the catheter is stressed.

Hypertension and brain oedema: an experimental study on acute and chronic hypertension in the rat.

To determine under what circumstances hypertension is associated with brain oedema, the specific gravity of the brain was measured in acutely hypertensive, renal hypertensive and spontaneously hypertensive rats. Maximum mean arterial pressure (MAP) in acute hypertension induced by intravenous amphetamine or bicuculline was 171 +/- 5 and 181 +/- 5 mmHg respectively. In spite of pronounced extravasation of Evans blue-albumin, there was no decrease in specific gravity except in the diencephalon in rats given bicuculline (p less than 0.05). Cortical and cerebellar samples from renal hypertensive rats (MAP 174 +/- 14 mmHg) were lighter than corresponding regions in normotensive rats (p less than 0.001) although the brains showed little or no macroscopic extravasation of Evans blue-albumin. Neither macroscopic protein leakage nor increase in water content was observed in brains from spontaneously hypertensive rats (MAP 210 +/- 5 mmHg). It is concluded that renal hypertension is more likely to lead to brain oedema than spontaneous genetic hypertension or acute hypertension.

Cannula thrombophlebitis: a study in volunteers comparing polytetrafluoroethylene, polyurethane, and polyamide–ether–elastomer cannulae

Cannulae made of polytetrafluoroethylene (PTFE: n = 11), thermoplastic polyether–urethane (TPEU: n = 11), and a new test material, polyamide–ether–elastomer (XLON: n = 10) were inserted into the veins of the dorsum of the hand in 32 healthy volunteers (10 women and 22 men), 21–50 years old. The cannulae were intended to be left in place for 5 days. No infusion was given and the dressings were not exchanged. The resulting thrombophlebitis, defined as two or more of the symptoms pain, redness, oedema and hardness, was estimated on a scale which took into account the incidence, location, intensity, and duration of the symptoms. Except for one volunteer in the XLON group, all the volunteers developed thrombophlebitis, generally observed on the third day of cannulation, and being more frequent and intense over the cannulae (P < 0.001) and at the tip (P < 0.01) than at the insertion sites. Pain and oedema were, on the whole, the most frequent and severe symptoms during the period of indwelling. After withdrawal, hardness was the most intense, and together with pain, the most long–lasting (up to 10 days) symptom. The differences between the materials in thrombophlebitis incidence and intensity were statistically significant only when each symptom was analysed separately. Thus, the PTFE cannulae caused more pain and hardness (probably because of greater platelet adhesion and a relatively greater stiffness), while the TPEU and XLON cannulae produced more periphlebitis (redness and oedema), probably because of potentially irritant and antigenic substances leaking from them (polyurethane oligomers and polyamide/polyethyleneglycol oligomers).

The Blood Brain Barrier in Renal Hypertensive Rats

Spontaneous hypertensive rats (SHR) are less prone to develop a dysfunction of the blood-brain barrier (BBB) when exposed to an abrupt increase in blood pressure than normotensive rats (NR), probably as a result of vessel wall hypertrophy and increased vessel wall to lumen ratio. Hemodynamic studies have indicated that structural adaptation develops early as a response to the increased pressure load in renal hypertensive rats (RHR). In the present study RHR (one renal artery constricted and the contralateral kidney intact) were subjected to acute hypertension induced by bicuculline, a drug that induces an abrupt increase in blood pressure concomitant with pronounced cerebral vasodilatation. Protein leakage in the brain, as indicated by Evans blue-albumin and 125IHSA (human serum albumin) extravasation, was not reduced in RHR compared to NR. The cerebrovascular permeability was slightly but significantly (p < 0.01) increased in RHR even in the absence of further blood pressure manipulation. No neurological symptoms were observed in conscious RHR when the BBB dysfunction was aggravated by hypercapnia. The increased cerebrovascular permeability in RHR cold be due to a lower degree of structural adaptation in RHR compared to SHR and/or to some permeability-increasing humoral factor in renal hypertension.