Kenneth M. Sutin

Guidelines for the Treatment of Acidaemia with THAM

SummaryTHAM (trometamol; tris-hydroxymethyl aminomethane) is a biologically inert amino alcohol of low toxicity, which buffers carbon dioxide and acids in vitro and in vivo. At 37°C, the pK (the pH at which the weak conjugate acid or base in the solution is 50% ionised) of THAM is 7.8, making it a more effective buffer than bicarbonate in the physiological range of blood pH. THAM is a proton acceptor with a stoichiometric equivalence of titrating 1 proton per molecule. In vivo, THAM supplements the buffering capacity of the blood bicarbonate system, accepting a proton, generating bicarbonate and decreasing the partial pressure of carbon dioxide in arterial blood (paCO2). It rapidly distributes through the extracellular space and slowly penetrates the intracellular space, except for erythrocytes and hepatocytes, and it is excreted by the kidney in its protonated form at a rate that slightly exceeds creatinine clearance. Unlike bicarbonate, which requires an open system for carbon dioxide elimination in order to exert its buffering effect, THAM is effective in a closed or semiclosed system, and maintains its buffering power in the presence of hypothermia.THAM rapidly restores pH and acid-base regulation in acidaemia caused by carbon dioxide retention or metabolic acid accumulation, which have the potential to impair organ function.Tissue irritation and venous thrombosis at the site of administration occurs with THAM base (pH 10.4) administered through a peripheral or umbilical vein; THAM acetate 0.3 mol/L (pH 8.6) is well tolerated, does not cause tissue or venous irritation and is the only formulation available in the US. In large doses, THAM may induce respiratory depression and hypoglycaemia, which will require ventilatory assistance and glucose administration.The initial loading dose of THAM acetate 0.3 mol/L in the treatment of acidaemia may be estimated as follows: THAM (ml of 0.3 mol/L solution) = lean body-weight (kg) × base deficit (mmol/L). The maximum daily dose is 15 mmol/kg for an adult (3.5L of a 0.3 mol/L solution in a 70kg patient).When disturbances result in severe hypercapnic or metabolic acidaemia, which overwhelms the capacity of normal pH homeostatic mechanisms (pH ≤7.20), the use of THAM within a ‘therapeutic window’ is an effective therapy. It may restore the pH of the internal milieu, thus permitting the homeostatic mechanisms of acid-base regulation to assume their normal function. In the treatment of respiratory failure, THAM has been used in conjunction with hypothermia and controlled hypercapnia. Other indications are diabetic or renal acidosis, salicylate or barbiturate intoxication, and increased intracranial pressure associated with cerebral trauma. THAM is also used in cardioplegic solutions, during liver transplantation and for chemolysis of renal calculi.THAM administration must follow established guidelines, along with concurrent monitoring of acid-base status (blood gas analysis), ventilation, and plasma electrolytes and glucose.

Acute biceps compartment syndrome associated with the use of a noninvasive blood pressure monitor.

A 29-yr-old man sustained a tibia-fibula fracture with extensive bone loss after a motorcycle accident. He had no past medical history and his vital signs were normal. He was mesomorphic, 168 cm tall, weighed 70 kg, and his physical examination was unremarkable. The patient underwent a microvascular free fibular bone transfer of the left fibula to the right tibia. Prior to surgery, a 125-mm wide NIBP cuff was wrapped firmly around the upper left arm. Cuff size was determined by visual inspection to be approximately 40% of the midarm circumference. The NIBP was cycled every 5 min (Hewlett Packard Component Monitoring System NIBP module 1008-B; Hewlett-Packard, Palo Alto, CA). A right arm vein was cannulated with a 16-gauge catheter. General anesthesia was induced with intravenous midazolam, droperidol, fentanyl, d-tubocurarine, thiopental, and pancuronium and the trachea was intubated via direct laryngoscopy. Sixty minutes after induction of anesthesia, a 20-gauge right radial arterial catheter was inserted, and the NIBP was cycled every 30 min. He was placed in the left lateral decubitus position where he remained for 9 h. The nondependent left arm was supported by a chest roll in a 60” semiflexed position. The NIBP tubing was unobstructed. Anesthesia was maintained with 0,, N,O, isoflurane, fentanyl, and pancuronium. The blood pressure (BP) varied between 110/60 and 120170 mm Hg, except for 10 min when it reached a minimum of 80/60 mm Hg. He received 8800 mL of crystalloid, 7 U of packed red blood cells, and 1000 mL of 5% albumin; blood loss was 2000 mL; urine output 1740 mL. The initial hematocrit was 40%, reached a minimum of 24%, and was 30% at the end of surgery. Arterial blood gases and electrolytes were normal. Muscle

A rat sciatic nerve model for independent assessment of sensory and motor block induced by local anesthetics.

The purpose of this study was to develop a reliable model to independently quantify motor and sensory block produced by local anesthetics. The sciatic nerve was blocked in 52 rats by injecting 0.2 mL of 0.125%, 0.25%, 0.5%, or 0.75% bupivacaine (n = 13 for each concentration). Accurate needle placement was achieved using a nerve stimulator at 0.2 mA and 1 Hz. Ten control rats received 0.9% saline (n = 5) or sham nerve stimulation (n = 5). Motor block was assessed by measuring hindpaw grip strength with a dynamometer. Sensory block was determined by measuring hindpaw withdrawal latency from radiant heat. The intensity of both motor and sensory block measured at 30-min intervals was plotted against time until full recovery to obtain the area under the curve. Intergroup comparisons using analysis of variance showed increasing area under the curve with increasing concentrations of bupivacaine for motor blocks (P < 0.05 for all intergroup comparisons except 0.5% vs 0.75%) and sensory blocks (P < 0.05 for all intergroup comparisons). Normal saline or sham nerve stimulation did not result in any motor or sensory block.

The place of THAM in the management of acidemia in clinical practice.

TITRATING agents should only be used to correct acidemia after attempts to correct the underlying causes of this life-threatening condition have failed. This requires optimization of: ventilation CO2 removal, circulation to promote blood-tissue exchange, metabolic status (in, for example, diabetes) urinary function with hemodialysis if necessary. If these measures are ineffective, one can use buffers to normalize pH until homeostasis is restored. For example, nonbicarbonate buffers are indicated in severe bronchospasm (status asthmaticus) to reduce PaCO2 and restore adrenergic mediated bronchodilatation (1).

Difficult Airway Management in a Patient with Traumatic Asphyxia

as a backup. Initially, topical airway anesthesia (10% lidoCaine hydrochloride spray) and intravenous sedation (midazolam 3 mg) were given, and an awake tracheal intubation was attempted using direct laryngoscopy. The patient became more agitated, and his airway became obstructed. Attempted bag-valve-mask ventilation was unsuccessful. The surgical team, who had already prepared the anterior aspect of the neck with betadine solution, was informed that an emergency cricothyroidotomy may be required. Thiopental (125 mg) and succinylcholine (120 mg) were administered. After induction, bag-valve-mask ventilation with oropharyngeal airway could be performed, but orotracheal intubation, attempted by a trauma anesthesia and critical care fellow, remained impossible because of severe pharyngeal and laryngeal edema. Cricothyroidotomy was performed immediately after this single attempt to tracheal intubation. Systemic blood pressure and heart rate did not change during airway management and subsequent positive pressure ventilation, and arterial blood analysis, performed shortly after endotracheal intubation with the patient receiving 100% oxygen, revealed a pH, of 7.24, Pace, 24 mm Hg, Pao, 320 mm Hg, and HCO, 15.8 mEq/L. Roentgenograms revealed a widened mediastinum, bilateral pleural effusions, and a 3-cm pubic diastasis. Bilateral tube thoracostomy was performed, and 300 mL of blood was drained. Approximately 45 min after arrival, the patient was transported to the operating room, where general anesthesia was maintained with 0,, N,O, and fentanyl, and an external pelvic fixator was applied. A diagnostic supraumbilical peritoneal lavage was negative. However, because of systemic hypotension @O/40 mm Hg) and a decreasing hemoglobin level (10.5 g/dL to 8.0 g/dL), he was resuscitated with 2 L lactated Ringer’s solution, 8 units of packed red blood cells,

Physiological and Pharmacological Interactions of Marihuana (THC) with Drugs and Anesthetics

THC is one of the 60 natural cannabinoids contained in the marihuana plant, which is psychoactive. It is a long-acting agent with multiple pharmacological effects. THC produces bronchodilation, but can also cause airway irritation. Marihuana smoke possesses toxic components, including carbon monoxide, tar, and carcinogens, which cause significant adverse pulmonary effects. THC causes a dose-dependent tachycardia, which is exacerbated by chronotropes and antagonized by (β-blockers, diazepam, and clonidine. Increases of blood pressure can occur, but orthostatic hypotension is also observed. Marihuana exacerbates angina pectoris in patients with exercise-inducible myocardial ischemia. Some patients report relief of neuropathic pain and discomfort after smoking marihuana or ingesting THC. However, in a controlled study on healthy volunteers who were studied by using the sensory decision theory to account for the psychoactive drug effects, marihuana smoking caused hyperalgesia. As an antiemetic, THC is much less effective than metoclopramide or 5-HT3 receptor antagonists, and it often causes unwanted psychoactive effects. THC is not effective as a premedication for anesthesia, and preoperative marihuana smoking exacerbates perioperative tachycardia. THC interacts with other drugs: it increases the depressant effects of sedatives and mitigates the effects of stimulants. In addition, severe adverse psychoactive side-effects have been observed when this agent is combined with barbiturates. In combination with opiates or ethanol, THC increases sedation and respiratory depression. The existing data indicate that marihuana or THC is not an acceptable adjunct to anesthesia.

Receptor and Nonreceptor Membrane-Mediated Effects of THC and Cannabinoids

A strict chemical nomenclature is first proposed. It is based on the definitions of cannabinoids, psychoactive (THC) and nonpsychoactive (CBD, CBN, and THC-11 oic acid), and of identified receptors (AEA and G protein) and their physiological ligands (arachidonyl ethanolamine [AEA] and arachidonyl diglycerol [2-AG]). THC is the only natural cannabinoid that interacts with a receptor protein in a stereospecific fashion, a property which is associated with its psychoactivity. Other natural, nonpsychoactive cannabinoids, CBN and CBD, vary over a wide range of concentration in marihuana preparations and antagonize the effects of THC. They also possess biological properties, activating membrane enzymes (phosphorylase and acyltransferase) that increase arachidonic acid biosynthesis.

Clinical potency of calcium channel blockers in asthma may be related to their inhibition of receptor-mediated phasic responses in vitro.

The calcium channel blockers (CCB) have been clinically effective in exercise-induced asthma. The completeness of protection with the CCB might be related specifically to inhibition of Ca2+ influx or release. To examine this hypothesis, the rank order of potency of inhibition of the CCB, nicardipine, diltiazem and verapamil on the steady-state and kinetic parameters of the phasic and tonic responses to the muscarinic receptor agonist carbachol (10 microM) and KCl (40 mM) in the intact isolated guinea-pig trachea was determined. The Ca2+ channel agonist Bay K 8644 was also examined for its effects on intracellular Ca2+. Nicardipine abolished the KCl response at both 0.1 microM and 1 microM concentrations. The amplitude of the KCl response was inhibited equally by 1 microM diltiazem (61% inhibition) and 1 microM verapamil (68% inhibition). The rate constant of onset of the KCl response was similarly inhibited 60% by diltiazem and 66% by verapamil. Nicardipine abolished the carbachol phasic response at the 1 microM concentration. The amplitude of the phasic response was inhibited equally by 0.1 microM nicardipine (61.3% inhibition), 1 microM diltiazem (64.5% inhibition) and 1 microM verapamil (71% inhibition). The rate constant of decay of the phasic response was inhibited equally by 0.1 microM nicardipine (43% inhibition) and 1 microM diltiazem (29% inhibition). The rate constant of onset of the phasic response was unaffected by nicardipine, diltiazem and verapamil. Only 1 microM nicardipine inhibited the amplitude and rate constant of onset of the tonic response. The only effect of Bay K 8644 (1 microM) was to increase the phasic response amplitude. The CCB demonstrate a similar order of potency for inhibition of the phasic responses and clinical efficacy of the CCB in exercise-induced asthma (nicardipine > verapamil > diltiazem).(ABSTRACT TRUNCATED AT 250 WORDS)

Psychoactive cannabinoids and membrane signaling.

THC‐like psychoactive cannabinoids permeate the lipid bilayer of the membrane, altering its physicochemical properties and activating phospholipases. As a result, an increased production of arachidonic acid occurs with its cascade of eicosanoids, including prostaglandins. In addition, THC and its psychoactive derivatives bind within the membrane in a stereospecific fashion, to a transmembrane G protein coupled receptor (GPCR) for which THC has a much higher affinity than the natural ligands, arachidonylethanolamide (AEA) and 2‐arachidonyglycerol (2‐AG). These natural lipid ligands may be considered signaling molecules which are generated in the membrane lipid bilayer. THC alters the physicochemical disposition of the lipid bilayer and interacts with the integral membrane protein receptors through alteration of the boundary lipid. This effect is distinct from the mechanism resulting from its persistent binding to a G protein coupled transmembrane receptor. THC does not interact directly with neurotransmitter receptors but alters their pharmacological response in an allosteric fashion. It is proposed that the binding of AEA and 2‐AG to the G protein coupled transmembrane receptor possesses a physiological function which is to regulate the signaling between boundary lipids and membrane receptors in response to extracellular signals. AEA and 2‐AG are eicosanoid signaling molecules which modulate the activity of G protein coupled transmembrane receptors. AEA and 2‐AG should not be identified with synthetic ligand molecules dubbed ‘endogenous cannabinoids’ which are ‘xenobiotics’ with no physiological regulating function. THC deregulates persistently a basic signaling mechanism of the membrane lipid bilayer and of its integrated receptors with resulting impairment of cellular function of brain, heart and male gonads. Copyright

A molecular basis of the therapeutic and psychoactive properties of cannabis (Δ9-tetrahydrocannabinol)☆

All of the therapeutic properties of marihuana (analgesic, antiemetic, appetite stimulant, antiglaucoma) have been duplicated by the tetrahydrocannabinol (THC) molecule or its synthetic derivatives. Today, the molecular mechanisms of action of these compounds have led to a general understanding of the pharmacological effects of marihuana and of its therapeutic properties. These mechanisms involve the specific binding of THC to the 7-transmembrane (7TM) domain G protein-linked receptor, a molecular switch which regulates signal transduction in the cell membrane. The natural ligand of the 7TM receptor is an eicosanoid, arachidonylethanolamide (AEA), generated in the membrane and derived from arachidonic acid. THC acts as a substitute ligand to the 7TM receptor site of AEA. THC would deregulate the physiological function of the 7TM receptor and of its ligand AEA. As a result, the therapeutic effects of the drug may not be separated from its adverse psychoactive and cardiovascular effects. The binding of THC to the 7TM receptor site of AEA induces allosteric changes in the receptor sites of neurotransmitter and opiates resulting in variable interactions and pharmacological responses. The pharmacokinetics of THC with its prolonged storage in fat and its slow release result in variable and delayed pharmacological response, which precludes precise dosing to achieve timely therapeutic effects. The experimental use of THC and of its synthetic analogues, agonists, and antagonists has provided novel information in the nature of molecular signaling in the cell membrane. As a result, the relationships between allosteric receptor responsiveness, molecular configuration of proteins, and physiological regulation of cellular and organ function may be further investigated.