Interpretation and advice
An experienced hospital toxicologist is expected not only to provide valid analytical data, but also to assist the clinician in relating the findings to a particular case of poisoning. This may be quite straightforward when the presence of a high concentration of a drug or poison is consistent with the patient’s symptoms and the circumstantial evidence. In other cases, factors such as the patient’s age, sex, health and previous exposure must be taken into account. For example, addicted patients may have developed a tolerance to extremely high concentrations of opiates, benzodiazepines and ethanol, and exhibit relatively mild toxicity. An elderly invalid with respiratory problems is far more susceptible to an overdose of a central depressant drug than a healthy young adult, and so may have life-threatening symptoms with only moderate plasma concentrations. The route of administration (inhalation, oral ingestion, intra venous injection, etc.) can have a very significant effect on the subsequent toxicity, which must also be taken into account when interpreting plasma concentrations. Mixed overdoses of drugs and alcohol are common, and synergistic reactions can confuse the clinical picture. The hospital toxicologist must therefore develop a good background knowledge of drug interactions. However, there are situations in which the analytical results fail to offer an adequate explanation. This can result from mistakes in sample collection, for example when blood samples taken from an arm being used to infuse a therapeutic agent may have very high concentrations of that agent because of contamination. Cleaning the skin with alcoholbased swabs prior to venepuncture can result in apparently huge blood alcohol concentrations. Systems for collecting and referring samples to the laboratory can occasionally break down and the samples received and analysed (with negative results) may be from the wrong patient, or trough and peak levels may be interchanged. Negative results on the correct samples must also be interpreted with caution. The patient may not be poisoned after all and the clinical effects may be caused by an organic disorder. Alternatively, the toxic agent responsible is not detected, which may instigate a wider analytical search or application of a more sensitive assay. A list of therapeutic and toxic concentration ranges for drugs is given in Table 8.8. The hospital toxicologist may also be asked to apply toxicokinetic principles to the quantitative data to answer questions raised by the clinician; examples in which this is relevant are described below. How much (A) of the poison is still in the body at a serum concentration C?
A=C x Vd (L/kg body mass) x body mass (kg)
where Vd is the volume of distribution. How long will it take for a measured serum concentration (C0) to decrease to below the toxic concentration (Ctox)?
Ctox=C0 x e-ket
where ke is the elimination constant, 0.693/t1/2. If the elimination is not saturated, the kinetic parameter ke of the patient can be calculated as follows, using two serum concentrations measured during the elimination phase:
Clearance CL= k x Vd
where Vd is volume of distribution.
What is the efficiency of an extracorporeal elimination treatment? Severe cases of intoxication sometimes require extracorporeal elimination treatments, such as haemodialysis or haemoperfusion. For the clinician it is important to have an estimate of how many hours the dialysis or haemoperfusion has to be continued and when the next blood should be withdrawn. The efficiency of haemodialysis (or haemoperfusion) can be determined as follows:
• measure the blood flow-rate (mL/min) through the artificial kidney
• as the drug levels are measured in plasma and the drug is cleared from the plasma, the blood flow-rate has to be converted into the plasma flow-rate [blood flow-rate (1 haematocrit)].
• measure the drug plasma levels in samples taken before (Cbef) and after (Caft) the artificial kidney
• [(Cbef-Caft)/Cbef x blood flow x [1-haemat-ocrit] = clearance (mL/min)
• this extracorporeal clearance has to be added to the physiological clearance of the poisoned patient: (Clown=CLextr = CLtotal) • the half-life time during extracorporeal clearance is: (ln 2)/k=0.69Vd /CLtotal.
As an alternative to these formulae, the toxicologist can use a commercially available toxicokinetic or pharmacokinetic software program. The pharmacokinetics software package MW/ Pharm (Mediware, University of Groningen, The Netherlands) is very suitable and flexible for both therapeutic drug monitoring (TDM) and toxicological calculations. AutoKinetic by SW Tönnes, Frankfurt, Germany, is a less comprehensive program that uses Microsoft Excel.
