British Journal of Anaesthesia 1994; 73: 564-567

CORRESPONDENCE

Inhaled nitric oxide after cardiac surgerySir,—I read with interest the recent paper by Snow and colleagues[1] describing their findings on the use of nitric oxide aftercardiopulmonary bypass in a small group of patients. However,there were several problems with their study.

The number of patients studied was too small to draw firmconclusions, especially with regard to the negative results. AU buttwo variables in the mitral valve group showed no statisticallysignificant changes. Furthermore, the definition of pulmonaryhypertension used in the study was mean pulmonary arterypressure (PAP) greater than 20mmHg; this is a more lenientdefinition than their own reference [2] and that used by others [3].This resulted in very little difference between the two groupsbefore treatment. Their description of the eight CABG patients ashaving normal pulmonary vascular resistance (PVR) (less than246 dyn s cm"' before treatment) implies that four of the ninemitral patients (fig. 1) also had normal PVR. No comment wasmade on the fact that the only patients to respond dramaticallyhad the highest PVR values initially. The fact that the absolutechange in PAP is proportional to initial pressure has beendemonstrated previously [4] and is minimal in people with normalPVR [5].

The use of median values with such small samples sizes resultedin impressive change in PVR in table I, which docs not appear asimpressive as illustrated in figure 1 for patients undergoing mitralvalve surgery.

Methaemoglobin concentrations were apparently measured butno mention was made of the concentrations detected. Similarly,the concentration of nitrogen dioxide detected was not mentioned.As the ventilator used was not described, it is not possible toestimate the time that nitric oxide was mixed with oxygen. Ifmixing was before a ventilator with a bellows (e.g. Siemens 900C)then a relatively prolonged mixing period may have occurred. Arecent report describes a system for introducing nitric oxide in theinspiratory limb [6].

It is unfortunate that two patients were receiving a nitric oxidedonor (sodium nitroprusside) during the study and that anunstated number received this drug until an unspecified timebefore commencement of measurements.

The conclusions with regard to nitric oxide acting as apulmonary vasodilator in patients with pulmonary hypertensionmay be correct, but a larger study in patients with higherpressures is needed to delineate the size and nature of the effect inthose patients in whom pulmonary hypertension is a clinicalproblem after cardiopulmonary bypass.

I. R. JENKINSDepartment of Anaesthesia

Faculty of MedicineUniversity of British Columbia

Vancouver, Canada

1. Snow DJ, Gray SJ, Ghosh S, Foubert L, Oduro A,Higenbortom TW, Wells FC, Latimer RD. Inhaled nitricoxide in patients with normal and increased pulmonaryvascular resistance after cardiac surgery. British Journal ofAnaesthesia 1994; 72: 185-189.

2. Loscalzo J. Endothelial dysfunction in pulmonary hyper-tension. New England Journal of Medicine 1992; 327:117-119.

3. Girard C, Lehot JJ, Pannetier JC, Filley S, Ffrench P,Estanove S. Inhaled nitric oxide after mitral valve replace-ment in patients with chronic pulmonary artery hypertension.Anesthesiology 1992; 77: 880-883.

4. Rich GF, Murphy GD, Roos CM, Roger MS, Johns A.Inhaled nitric oxide selective pulmonary vasodilation incardiac surgical patients. Anesthesiology 1993; 78: 1028-1035.

5. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM.Inhaled nitric oxide: a selective pulmonary vasodilatorreversing hypoxic pulmonary vasoconstriction. Circulation1991; 83: 2038-2046.

6. Watkins DN, Jenkins IR, Rankin J, Clarke GM. Inhalednitric oxide in severe acute respiratory failure—its use in

intensive care and a description of a delivery system.Anaesthesia and Intensive Care 1993; 6: 861-866.

Sir,—We read with interest the recent article by Dr Snow andcolleagues [1] which suggested that nitric oxide induced areduction in pulmonary vascular resistance (PVR) in patients withpre-existing pulmonary hypertension. This effect was not seen inpatients who had normal pulmonary pressures.

The study period was within 2 h of operation. The authorsadmitted patients to the study when their haemodynamic variablesdid not fluctuate by more than 5% over a 5-min period.Circulatory variability may persist in these patients for some timeafter cardiopulmonary bypass. Given that some of the patients inthe CABG group, at the time of entry into the study (Tl) had, bythe study definition, elevated pulmonary pressures (SPAP> 30 mm Hg, MPAP > 20 mm Hg), while some patients in theMVR group had relatively normal pressures, do the authors feelthat: (i) the period of stabilization was adequate? or (ii) that thepressures measured at the start of the study period accuratelyreflected the patients' normal pulmonary pressures?

On close examination of the median figures tabulated in thearticle, there appears to be a difference of 23 % in mean PAPpressures before (Tl) and during (T3) exposure to nitric oxide inthe CABG group. Although this was not statistically significant,we wonder if a larger study would reveal a similar degree ofsignificance to that documented in the MVR group.

Nitric oxide is being studied increasingly as an agent whichproduces a reduction in pulmonary vascular resistance in a varietyof conditions. The effect is transient and should disappear rapidlyafter discontinuation of the agent. This did not appear to be thecase in the MVR group 10 min after cessation of nitric oxide (T4).It is thus possible that other factors were contributing to thechange in PVR noted in this group during this inherently unstableperiod.

J. TARPEYB. LYONS

Our Lady's Hospital for Sick ChildrenCrumlin, Dublin, Ireland

1. Snow DJ, Gray SJ, Ghosh S, Foubert L, Oduro A,Higenbortom TW, Wells FC, Latimer RD. Inhaled nitricoxide in patients with normal and increased pulmonaryvascular resistance after cardiac surgery. British Journal ofAnaesthesia 1994; 72: 185-189.

Sir,—Thank you for the opportunity to reply to the commentsof Dr Jenkins and Drs Tarpey and Lyons on our articledemonstrating the effects of inhaled nitric oxide in patients withnormal and increased pulmonary vascular resistance (PVR) aftercardiac surgery [1].

The number of patients studied was in accordance with thesample size required for statistical validity and, therefore, wecannot accept Dr Jenkins' comment that the study was too smallto draw firm conclusions.

On close scrutiny, Dr Jenkins will find that the median valuesfor systolic (SPAP) and mean (MPAP) pulmonary arterialpressures taken as baseline values in the postoperative period inthe mitral valve group were 35 and 22 mm Hg, respectively, andthat MPAP before operation exceeded 20 mm Hg in thesepatients. This is no less lenient a definition than our reference [2];in fact, these values are in complete agreement with the definitiongiven in that reference (MPAP > 20 mm Hg, SPAP> 30 mm Hg). Dr Jenkins will find that the reference [3] he hasused to support his statement that the absolute change in PAPis "minimal in people with normal PVR" was in fart conductedin eight Suffolk lambs.

Unfortunately, our article failed to mention the fact thatmethaemoglobin concentrations showed no significant change.Details of our nitric oxide delivery system are given below. Nitricoxide (10000 ppm in nitrogen) from a cylinder was pre-dilutedwith nitrogen to give a mixture of 400 ppm before it was added to

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Correspondence 565

oxygen-air, before the Brompton Manley ventilator. The con-centration of nitrogen dioxide was measured in the inspiratorytubing just before the patient and was always less than 2 ppm. Weare concerned that Dr Jenkins was unaware of the potentialdangers of the system of introducing a high concentration of nitricoxide as a continuous flow into the inspiratory limb of anintermittent flow ventilator [4]. This technique allows a bolus ofhigh concentration nitric oxide to be delivered to the patientwhich cannot be measured with the slow response analysers incurrent use.

In order to demonstrate this danger of inadequate mixing, wehave tried to simulate the dynamics of the system described [4].In the laboratory using a test lung, we substituted carbon dioxidefor nitric oxide because we have a capnograph with a sufficientlyrapid response. Adding carbon dioxide before the ventilator givesadequate mixing and consequently the expected concentration. Incontrast, adding carbon dioxide to the inspiratory limb can givepeak concentrations of three to five times the expected con-centration. Paradoxically, mixing before the ventilator delivers alower concentration of nitrogen dioxide to the patient: althoughthe transit time is longer, mixing is better and the dispersal of thehigh concentration is more rapid.

We do appreciate the point that haemodynamic variables areinherently unstable in the early period after cardiac surgery andthat changes in baseline measurements may potentially flawresults. We set out to study the efficacy of inhaled nitric oxide inpostoperative cardiac surgical patients; within the constraints ofsafe and ethical practice we believe the design of our study wassuited to this purpose. We hope that other groups may now feelable to conduct such a study in patients with much higherpulmonary vascular pressures and resistances with all theattendant risks. We felt that including more severely diseasedpatients in one of the earliest clinical studies of nitric oxide wasunjustifiable.

S. GHOSHD. J. SNOW

A. H. MOORSA. ODURO

R. D. LATIMERDepartment of Anaesthesia

Papworth Hospital NHS TrustCambridge

1. Snow DJ, Gray SJ, Ghosh S, Foubert L, Oduro A,Higenbottam TW, Wells FC, Latimer RD. Inhaled nitricoxide in patients with normal and raised pulmonary vascularresistance after cardiac surgery. British Journal of Anaesthesia1994; 72: 185-189.

2. Loscalzo J. Endothelial dysfunction in pulmonary hyper-tension. New England Journal of Medicine 1992; 327:117-119.

3. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM.Inhaled nitric oxide: A selective pulmonary vasodilatorreversing hypoxic pulmonary vasoconstriction. Circulation1991; 83: 2038-2047.

4. Watkins DN, Jenkins IR, Rankin JM, Clarke GM. Inhalednitric oxide in severe acute respiratory failure—its use inintensive care and description of a delivery system. An-aesthesia and Intensive Care 1993; 21: 861-866.

Postoperative deliriumSir,—I have read with interest the article on treatment ofpostoperative delirium with supplementary oxygen by Aakerlundand Rosenberg [1]. The results are interesting, but not surprising.The authors mentioned that delirium is a non-specific syndromecaused by widespread cerebral dysfunction, which may be a resultof a variety of factors. However, they do not mention that acutedepression may be a cause of this delirium. This is important tohighlight as it is easily treated [2-4].

J. G. BROCK-UTNEDepartment of Anesthesia

Stanford University School of MedicineStanford, CA, USA

1. Aakerlund LP, Rosenberg J. Postoperative delirium: treat-ment with supplementary oxygen. British Journal of An-aesthesia 1994; 72: 286-290.

2. Komfeld DS, Zimberg S, Malm JR. Psychiatric complicationof open heart surgery. New England Journal of Medicine 1965;273: 287-291.

3. Brock-Utne JG, Cheetham RWS, Goodwin NM. Psychiatricproblems in intensive care. Anaesthesia 1976; 31: 380-384.

4. Brock-Ume JG, Goodwin NM, Hicks JC. Acute confusionalstates and depression treated with maprotiline mesylate.South African Medical Journal 1979; 55: 641.

Ventilatory response to hypoxiaSir,—I wish to comment on Dr Goodman's excellent andinteresting editorial [1] "Volatile agents and the ventilatoryresponse to hypoxia".

In the editorial I was quoted in a personal communication notesaying, "that there is no important depression specifically of thehypoxic response". The quotation is correct but needs clari-fication. Hypoxic ventilatory responses are traditionally expressedas changes in minute ventilation related to the degree of hypoxia.In our studies [2-6] we found that by separating minute ventilationresponses into changes in tidal volume and ventilatory frequency,hypoxic ventilatory responses are achieved by increased tidalvolumes (motor response) in the awake state and by increasedventilatory frequencies (chronotropic response) during isofluraneanaesthesia [6]. We therefore emphasize that motor and timingresponses have to be evaluated separately. The resulting minuteventilation seems, in our hands, to be the same in awake andanaesthetized subjects, at least when a poikilocapnic approach isused. These results, from studies in humans, are currently beingscrutinized in ongoing investigations in our laboratory.

S. LINDAHLDepartment of Anaesthesiology and Intensive Care

Karolinska InstituteStockholm, Sweden

1. Goodman NW. Volatile agents and the ventilatory responseto hypoxia. British Journal of Anaesthesia 1994; 72: 503-505.

2. Sjogren D, Ebberyd A, Sollevi A, Lindahl SGE. Ventilatoryresponses to hypoxia in awake and anesthetized humans.Anesthesiology 1991; 75: A1102.

3. Lindahl SGE, SjSgren D, Sollevi A. Isoflurane anesthesia(0.6 MAC) and hypoxic ventilatory response in humans.Anesthesiology 1993; 79: A1201.

4. Sollevi A, Sjogren D, Lindahl SGE. Effect of isofluraneanesthesia on hypoxic and hypercapnic ventilatory responsein humans. Anesthesiology 1993; 79: A1202.

5. Sjogren D, Sollevi A, Ebbcryd A, Lindahl SGE. Poikilo-capnic hypoxic ventilatory response in humans during 0.85MAC isoflurane anaesthesia. Acta Anaeslhcsiologica Scan-dinavica 1994; 38: 149-155.

6. Sjogren D, Sollevi A, Ebberyd A, Lindahl SGE. Isofluraneanaesthesia (0.6 MAC) and hypoxic ventilatory responses inhumans. Acta Anaesthesiologica Scandinavica 1994; (in press).

Sir,—Professor Lindahl makes an important point. Almost all themathematical models of ventilation ignore riming: for example, inCarley and Shannon's model [1] "breathing frequency is chosena priori and remains constant." We also know that halothanc,enflurane and isoflurane are all ventilatory depressants but do nothave identical effects on ventilatory control. There is still much tolearn about the effects of anaesthesia on human breathing.

N. W. GOODMANUniversity Department of Anaesthesia

Southmead Hospital, Bristol

1. Carley DW, Shannon DC. A minimal mathematical model ofhuman periodic breathing. Journal of Applied Physiology1988; 65: 1400-1409.

Risk of aspiration with the laryngeal maskSir,—We read with interest the study by Akhtar and Street on therisk of aspiration with the laryngeal mask airway (LMA) [1]. Fiftypatients were allocated randomly to receive either IPPV orspontaneous ventilation. One patient in the spontaneous venti-lation group demonstrated dye staining of the pharynx, anda second patient in the IPPV group, undergoing diagnostic

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